Method for producing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid

Abstract

The present invention relates to the technical field of drug synthesis, specifically to a method for preparing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid. The method involves steps such as protection, condensation, and hydrolysis. Through screening of hydroxyl-protecting reagents for the starting material, i.e., 2-(4-trifluoromethyl)phenethyl alcohol, and optimization of other process parameters, the content of meta-isomer impurities and divalently substituted impurities in the target product can be effectively controlled, resulting in significantly improved product quality and reaction yields. The improved product quality can meet the relevant requirements for manufacturing research (Figure 1).

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis methods, and relates to the synthesis of drugs for treating Alzheimer's disease. In particular, it relates to a method for producing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid.

Background Art

[0002] This application was filed with the China National Intellectual Property Administration on December 8, 2020, and claims priority based on Chinese Patent Application No. 202011445339.4, entitled "Method for Producing 2-Hydroxy-5-[2-(4-(Trifluoromethylphenyl)Ethylamino)]Benzoic Acid". All the contents disclosed in the specification and drawings of this application are incorporated into this application.

[0003] 2-Hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid is a novel necroptosis inhibitor developed by the Korean pharmaceutical company GNT Pharma, which can effectively treat nervous system diseases such as Alzheimer's disease and Parkinson's syndrome, and is highly evaluated clinically.

[0004] Currently, there are few reports on the synthesis method of this compound, and the associated processes are complex, the raw materials are expensive, and the practical applications are limited. Wu Yuliang et al. reported an industrially expandable synthetic route for the production of the target product applicable to mass production, achieved through the condensation and hydrolysis of 2-(4-trifluoromethyl)phenethylmethanesulfonate (compound 4) and methyl 5-aminosalicylate (compound 6) (Wu Yuliang, Lu Xin et al., Synthesis of an anti-Alzheimer's disease drug 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid [J], Chinese Journal of New Drugs, 2012, 21 (16): 1930-1932). However, the biggest problem with this route is that 2-(4-trifluoromethyl)phenethylmethanesulfonate has poor stability, a low melting point (27-28°C), and is not easy to refine and purify. In particular, the meta-isomer impurity 2-(3-trifluoromethyl)phenethylmethanesulfonate is difficult to remove, and the content of the divalently substituted impurity methyl 2-hydroxy-5-[N,N-bis(2-(4-(trifluoromethyl)phenyl)ethyl)amino]benzoate, which is obtained from the condensation reaction, is high, and its hydrolysates flow into the final product, affecting the quality of the final product. Recently, with the increasing standards for quality control of active pharmaceutical ingredients (APIs), there are many problems with synthesis using 2-(4-trifluoromethyl)phenethylmethanesulfonate.

[0005] In order to resolve the problems present in the current process and to obtain a high-quality product, it is highly desirable to find a suitable intermediate to replace 2-(4-trifluoromethyl)phenethylmethanesulfonate. [Overview of the project] [Problems that the invention aims to solve]

[0006] [Technical problems] To overcome the drawbacks described above, the present invention provides a method for producing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid having high yield and high purity. [Means for solving the problem]

[0007] [Technical solutions] Specifically, the present invention provides a method for producing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid, comprising the following steps: 1) A step of obtaining compound II by reacting compound I with a protecting reagent,

[0008] [ka]

[0009] 2) The step of obtaining compound III by condensing compound II with methyl 5-aminosalicylate, and

[0010] [ka]

[0011] 3) A step in which compound III is hydrolyzed to obtain the target compound IV.

[0012] [ka]

[0013] Here, R is one of p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, and acetyl, preferably p-methylbenzenesulfonyl or benzenesulfonyl, and more preferably p-methylbenzenesulfonyl.

[0014] In the above manufacturing method, the protective reaction is carried out at 0 to 30°C, preferably at 20 to 25°C.

[0015] In the above-described manufacturing method, the protective reaction is carried out in a solvent, and the solvent is at least one of toluene, ethylbenzene, xylene, methylene chloride, and chloroform, preferably toluene.

[0016] Preferably, in the above manufacturing method, step (1) further comprises a step of purifying crude compound II.

[0017] More preferably, in the above manufacturing method, purification is carried out by crystallization, which is carried out by dissolution at 40-80°C and adiabatic crystallization at 0-40°C, preferably by dissolution at 50-60°C and adiabatic crystallization at 20-30°C, and the solvent used for the crystallization is at least one of ethyl acetate, n-hexane, n-heptane, toluene, methylene chloride, methanol, ethanol, isopropanol, and water, preferably n-heptane.

[0018] In the above manufacturing method, the condensation reaction is carried out at a temperature of 30 to 100°C, preferably 80 to 90°C.

[0019] In the above-described manufacturing method, the condensation reaction is carried out in a solvent, and the solvent is at least one of toluene, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran, preferably toluene.

[0020] In the above manufacturing method, the condensation reaction is carried out in the presence of a base, and the base is at least one of triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and pyridine, and preferably, it is triethylamine.

[0021] Preferably, in the above manufacturing method, step (2) further includes a step of forming a salt of the crude compound III using an acid or an aqueous solution thereof.

[0022] More preferably, in the above manufacturing method, the formation of the salt is carried out using an inorganic acid, and the inorganic acid is at least one of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, and preferably, it is sulfuric acid.

[0023] In the above manufacturing method, the hydrolysis reaction is carried out at a temperature of 60 to 100°C, preferably 80 to 85°C.

[0024] In the above manufacturing method, the hydrolysis reaction is carried out in the presence of an acid, which is sulfuric acid.

[0025] In the above manufacturing method, the hydrolysis reaction is carried out by nitrogen bubbling.

Advantages of the Invention

[0026] Together with the optimization of other process parameters, using a specific protecting reagent for protecting the hydroxy group of compound I (that is, 2-(4-trifluoromethyl)phenethyl alcohol), the method of the present invention can effectively remove meta-isomer impurities in step (1) and di-substituted impurities in step (2), and obtain 2-hydroxy-5-[2-(4-(trifluoromethyl)phenyl)ethylamino)]benzoic acid with a high yield and high purity, thereby meeting the conditions of high quality standards for APIs in manufacturing research.

Brief Description of the Drawings

[0027] [Figure 1] The chromatogram obtained by high-performance liquid chromatography (HPLC) of the target product prepared in Example 1 is shown. [Figure 2] The chromatogram obtained by high-performance liquid chromatography (HPLC) of the target product prepared in Example 2 is shown. [Figure 3] The chromatogram obtained by high-performance liquid chromatography (HPLC) of the target product prepared in Example 3 is shown. [Figure 4] The chromatogram obtained by high-performance liquid chromatography (HPLC) of the target product prepared in Example 4 is shown. [Figure 5] The chromatogram obtained by high-performance liquid chromatography (HPLC) of the target product produced in the comparative example is shown. [Modes for carrying out the invention]

[0028] The following description of the technical features is based on representative and specific embodiments of the present invention, but the present invention is not limited in any way to these embodiments and specific embodiments.

[0029] Unless otherwise expressly defined in this disclosure, the term “compound” as used herein encompasses all stereoisomeric forms, geometric isomeric (cis-trans isomeric) forms, tautomeric forms, and isotope-labeled forms of a compound.

[0030] Unless otherwise expressly defined in this disclosure, the numerical range expressed herein as “Numerical A–Numerical B” means the range that includes the endpoint values ​​A and B.

[0031] Unless otherwise expressly defined in this disclosure, the terms “above” or “below” used herein mean the range of numbers that include those numbers.

[0032] Unless explicitly defined in this disclosure, references to “some specific / preferred embodiments,” “other specific / preferred embodiments,” “embodiments,” etc., in this specification mean that certain elements (e.g., features, structures, properties, and / or characteristics) relating to that embodiment are included in at least one embodiment described herein and may or may not be present in other embodiments. It should be understood that elements can be combined in various embodiments in any preferred manner.

[0033] Unless explicitly defined in this disclosure, the term “plurality” as used herein means that there are two or more items referred to by that term.

[0034] The present invention will be described in detail below.

[0035] The present invention provides a method for producing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid having high yield and high purity.

[0036] The method described above includes the following steps: (1) A step of obtaining compound II by reacting compound I with a protective reagent,

[0037] [ka]

[0038] (2) The step of reacting compound II with methyl 5-aminosalicylate to obtain compound III,

[0039] [ka]

[0040] (3) A step in which compound III is hydrolyzed to obtain the target compound IV, 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid.

[0041] [ka]

[0042] Here, R is one of p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, and acetyl, preferably p-methylbenzenesulfonyl or benzenesulfonyl, and more preferably p-methylbenzenesulfonyl.

[0043] [Step (1)] Step (1) is to react compound I (i.e., 2-(4-trifluoromethyl)phenethyl alcohol) with a protecting reagent to obtain compound II (i.e., 2-(4-trifluoromethyl)phenethyl sulfonate or carboxylate).

[0044] In step (1), the selection of protecting groups plays a crucial role in removing meta-isomer impurities in this step and controlling divalently substituted impurities in step (2).

[0045] In one embodiment of the present invention, the protecting reagent used to protect compound I in step (1) may be any one of p-methylbenzenesulfonyl chloride, trifluoromethanesulfonyl chloride, acetyl chloride, benzenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride, or any one of the anhydrides thereof. Therefore, the protecting group (i.e., the R group) of compound II may be any one of p-methylbenzenesulfonyl, trifluoromethanesulfonyl, acetyl, benzenesulfonyl, and p-nitrophenylsulfonyl.

[0046] In a preferred embodiment of the present invention, the protective reagent used to protect compound I in step (1) may be p-methylbenzenesulfonyl chloride or benzenesulfonyl chloride.

[0047] In a more preferred embodiment of the present invention, the protective reagent used to protect compound I in step (1) may be p-methylbenzenesulfonyl chloride.

[0048] The intermediate 2-(4-trifluoromethyl)phenethylmethanesulfonate used in the prior art has poor stability and a low melting point, and is not easy to purify. In particular, isomeric impurities are difficult to remove, and the content of divalently substituted impurities in the condensation reaction is high, affecting the quality of the final product. In contrast, the intermediates obtained in the present invention using the protective reagents described above are 2-(4-trifluoromethyl)phenethyl p-methylbenzenesulfonate, 2-(4-trifluoromethyl)phenethyltrifluoromethanesulfonate, 2-(4-trifluoromethyl)phenethyl acetate, 2-(4-trifluoromethyl)phenethylbenzenesulfonate, and 2-(4-trifluoromethyl)phenethyl p-nitrobenzenesulfonate, respectively, which overcome the drawbacks of the aforementioned 2-(4-trifluoromethyl)phenethylmethanesulfonate. As a result, the final product, 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid, can be produced with high purity and high yield.

[0049] In one embodiment of the present invention, the protective reaction in step (1) is carried out at a low temperature.

[0050] In a preferred embodiment of the present invention, the protective reaction in step (1) is carried out at 0 to 30°C.

[0051] In a preferred embodiment of the present invention, the protective reaction in step (1) is carried out at 20-25°C.

[0052] In one embodiment of the present invention, the protective reaction in step (1) may be carried out in a solvent.

[0053] In a preferred embodiment of the present invention, the protective reaction in step (1) may be carried out in an organic solvent, the solvent of which may be at least one of toluene, ethylbenzene, xylene, methylene chloride, and chloroform.

[0054] In a preferred embodiment of the present invention, the protective reaction in step (1) may be carried out in toluene.

[0055] After the protective reaction in step (1) is complete, water is added to the system and stirred for layer separation. The separated organic phase is then concentrated under reduced pressure to obtain crude compound II, which is further purified to obtain high-purity compound II.

[0056] In one embodiment of the present invention, step (1) may further include a step of purifying crude compound II. Generally, the purification step may be carried out by crystallization. The choice of solvent used for crystallization has a significant effect on the removal of metaisomers in step (1).

[0057] In a preferred embodiment of the present invention, the solvent used for crystallization may be at least one of ethyl acetate, n-hexane, n-heptane, toluene, methylene chloride, methanol, ethanol, isopropanol, and water.

[0058] In a more preferred embodiment of the present invention, the solvent used for crystallization may be n-heptane.

[0059] Furthermore, when purifying crude compound II using a crystallization method, the crystallization temperature can be controlled to facilitate the removal of impurities and the precipitation of the target product. If the crystallization temperature is too high, it may affect the yield, and if the crystallization temperature is too low, it may reduce the purity of compound II.

[0060] In one embodiment of the present invention, the crystallization may be carried out by dissolution at 40-80°C and adiabatic crystallization at 0-40°C.

[0061] In a preferred embodiment of the present invention, the crystallization may be carried out by dissolution at 50-60°C and adiabatic crystallization at 20-30°C.

[0062] [Step (2)] Step (2) is to react compound II with methyl 5-aminosalicylate to obtain compound III (i.e., methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoate).

[0063] In step (2), the reaction temperature has a significant effect on the divalently substituted impurities, and as the temperature increases, the content of the divalently substituted impurities will increase significantly.

[0064] In one embodiment of the present invention, the condensation reaction in step (2) may be carried out at a temperature of 30 to 100°C.

[0065] In a preferred embodiment of the present invention, the condensation reaction in step (2) may be carried out at a temperature of 80 to 90°C.

[0066] In one embodiment of the present invention, the condensation reaction in step (2) may be carried out in a solvent.

[0067] In a preferred embodiment of the present invention, the condensation reaction in step (2) may be carried out in an organic solvent, the solvent of which may be at least one of toluene, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran.

[0068] In a more preferred embodiment of the present invention, the condensation reaction in step (2) may be carried out in toluene.

[0069] In one embodiment of the present invention, the condensation reaction in step (2) may be carried out in the presence of a base, the base of which may be at least one of triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, and pyridine.

[0070] In one embodiment of the present invention, the condensation reaction in step (2) may be carried out in the presence of triethylamine.

[0071] After the condensation reaction in step (2) is complete, water is added to the system and stirred for layer separation, and then the separated organic phase is concentrated under reduced pressure to obtain crude compound III.

[0072] Since crude compound III is difficult to obtain in solid form and cannot be immediately crystallized, it must be converted into a salt form that is advantageous for obtaining it as a solid and achieving the objectives of separation and purification through crystallization.

[0073] In one embodiment of the present invention, step (2) further comprises the step of forming a salt of crude compound III using an acid (or a solution thereof, preferably an aqueous solution thereof). Generally, the salt formation step may be carried out using an inorganic acid or an organic acid. Common inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Common organic acids include, but are not limited to, acetic acid, lactic acid, citric acid, malic acid, and tartaric acid.

[0074] In a preferred embodiment of the present invention, the acid used to form the salt may be one of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, or an aqueous solution of any of these at any concentration.

[0075] In a more preferred embodiment of the present invention, the acid used in the formation of the salt may be sulfuric acid or an aqueous solution thereof of any concentration.

[0076] Therefore, when the acid used to form the salt is sulfuric acid, the acid addition salt of compound III is preferably hemisulfate.

[0077] [Step (3)] Step (3) is to hydrolyze compound III (i.e., methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoate) or its acid addition salt (e.g., hemisulfate) to obtain the target compound IV (i.e., 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid).

[0078] In one embodiment of the present invention, the hydrolysis reaction in step (3) may be carried out at 60 to 100°C.

[0079] In a preferred embodiment of the present invention, the hydrolysis reaction in step (3) may be carried out at 80-85°C.

[0080] In one embodiment of the present invention, the hydrolysis reaction in step (3) may be carried out in the presence of an acid, which may be sulfuric acid or an aqueous solution thereof of any concentration.

[0081] In one embodiment of the present invention, the acid used for hydrolysis may be sulfuric acid.

[0082] To further increase the purity of the manufactured compound IV, activated carbon may be added for decolorization.

[0083] In one embodiment of the present invention, the hydrolysis reaction in step (3) may be carried out by nitrogen bubbling, which can further shorten the reaction time and improve the reaction conversion rate.

[0084] Furthermore, it should be noted that, unless otherwise specifically defined in this disclosure, in the production method of the present invention, each step involves detecting the endpoint of the reaction using an HPLC method, the reacting materials are generally reacted according to the chemical reaction stoichiometric ratio or an excess, and the amount of reaction solvent and / or catalyst can be adjusted according to the amount of reacting materials, specifically increasing as the amount of reacting materials increases and decreasing as the amount of reacting materials decreases.

[0085] To further understand the technical solutions of the present invention, the invention will be described in more detail with reference to the following specific embodiments; however, a person of ordinary skill should recognize that the present invention is not limited in any way to such embodiments. [Examples]

[0086] Example 1: (1) Preparation of 2-(4-trifluoromethyl)phenethyl p-methylbenzenesulfonate:

[0087] [ka]

[0088] To a 500 mL quantitative flask, toluene (230 g) and p-methylbenzenesulfonyl chloride (100 g, 0.53 mol) were added, stirred, and dissolved. The solution was then stored separately. To a 1 L reaction flask, toluene (140 g), 40 wt% sodium hydroxide aqueous solution (140 g, 1.4 mol), and 2-(4-trifluoromethyl)phenethyl alcohol (95 g, 0.5 mol) were added and cooled to 0-10°C. Next, the toluene aqueous solution of p-methylbenzenesulfonyl chloride was added dropwise. The reaction was then carried out at 20-25°C for 6 hours and monitored by gas chromatography (GC). After the reaction was complete, drinking water was added and the mixture was stirred for layer separation. The organic phase was concentrated under reduced pressure to obtain the concentrated crude product. The temperature was raised to 50-60°C, and n-heptane (170 g) was added dropwise. Next, the mixture was cooled to 20-25°C, crystallized, filtered by suction, and dried to obtain a dried product (163g) of the target compound with an HPLC purity of 99.6%, a meta-isomer impurity content of 0.03%, and a yield of 95%.

[0089] (2) Preparation of methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoate hemisulfate:

[0090] [ka]

[0091] 68 g, 0.20 mol, 2-(4-trifluoromethyl)phenethyl p-methylbenzenesulfonate, 35 g, 0.21 mol, toluene, and triethylamine were added to a 1 L reaction flask. The mixture was heated and maintained at 80-90°C for 14 hours. After a sample was taken and passed the test, the reaction was stopped. Drinking water was then added, and the mixture was stirred and separated into layers. The organic phase was concentrated under reduced pressure until no distillate remained. 160 g of methanol was added, stirred and dissolved, and the mixture was heated to 35-40°C. 23 g, 0.12 mol, 50 wt%, aqueous sulfuric acid solution was added dropwise. Next, the mixture was stirred for 15 minutes, gradually cooled to 25-30°C, and allowed to crystallize adiabatically over 1 hour. The mixture was then filtered by suction and dried to obtain hemisulfate of compound III with 99% HPLC purity and 86.3% yield (67 g, 0.17 mol).

[0092] (3) Production of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid:

[0093] [ka]

[0094] 300 g of 40 wt% aqueous sulfuric acid, 100 g of glacial acetic acid, and 77 g of hemisulfate of compound III were added to a 500 mL reaction flask. The temperature was raised to 80-85°C while nitrogen was added to the reaction solution, and the bubbling reaction was carried out for 4 hours. After sampling and passing through testing, activated carbon was added for decolorization, and the solution was filtered. The filtrate was gradually cooled to -5-5°C, and dried by suction filtration to obtain a dried product (58.4 g) of compound IV with 99.957% HPLC purity and a yield of 93%. No divalently substituted or meta-isomer impurities were detected (shown in Figure 1).

[0095] Example 2: (1) Preparation of 2-(4-trifluoromethyl)phenethylbenzenesulfonate:

[0096] [ka]

[0097] To a 500 mL quantitative flask, toluene (230 g) and benzenesulfonyl chloride (93 g, 0.53 mol) were added, stirred, and dissolved. The solution was then stored separately. To a 1 L reaction flask, toluene (140 g), 40 wt% aqueous sodium hydroxide solution (140 g, 1.4 mol), and 2-(4-trifluoromethyl)phenethyl alcohol (95 g, 0.5 mol) were added and cooled to 0-10°C. The toluene solution of benzenesulfonyl chloride was then added dropwise. The reaction was then carried out at 20-25°C for 8 hours and monitored by GC. After the reaction was complete, drinking water was added and the mixture was stirred for layer separation. The organic phase was concentrated under reduced pressure to obtain the concentrated crude product. The temperature was raised to 50-60°C, and a mixed solvent of ethyl acetate and n-heptane (150 g) was added dropwise. Next, the mixture was cooled to 20-25°C, crystallized, filtered by suction, and dried to obtain a dried product (145 g, 0.44 mol) of the target compound with 98% HPLC purity and 89% yield.

[0098] (2) Preparation of methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoate hemisulfate:

[0099] [ka]

[0100] 66 g, 0.20 mol, 2-(4-trifluoromethyl)phenethylbenzenesulfonate, 35 g, 0.21 mol, toluene, and 24 g, 0.24 mol, triethylamine were added to a 1 L reaction flask. The mixture was heated and maintained at 90-100°C for 12 hours. After sampling and testing were completed, the reaction was stopped. Drinking water was then added and the mixture was stirred for layer separation. The organic phase was concentrated under reduced pressure until the distillate was gone. 168 g, methanol, was added and stirred to dissolve it. The mixture was heated to 35-40°C, and 23 g, 0.12 mol, 50 wt%, aqueous sulfuric acid solution was added dropwise. Next, the mixture was stirred for 15 minutes, gradually cooled to 25-30°C, and allowed to crystallize adiabatically over 1 hour. The mixture was then filtered by suction and dried to obtain hemisulfate (62 g) of compound III with 98.5% HPLC purity and an 80% yield.

[0101] (3) Production of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid: 240 g of 40 wt% aqueous sulfuric acid, 80 g of glacial acetic acid, and 60 g of hemisulfate of compound III were added to a 500 mL reaction flask. The temperature was raised to 80-85°C while nitrogen was added to the reaction solution, and the bubbling reaction was carried out over 4 hours. After sample collection and testing were completed, activated carbon was added for decolorization, and the solution was filtered. The filtrate was gradually cooled to -5-5°C, held for 1 hour, filtered by suction, and dried to obtain a dried product (44.5 g) of compound IV with a yield of 91%, having an HPLC purity of 99.831%, a content of divalently substituted impurities of 0.025%, and a content of meta-isomer impurities of 0.033% (shown in Figure 2).

[0102] Example 3: (1) Preparation of 2-(4-trifluoromethyl)phenethylacetate:

[0103] [ka]

[0104] To a 500 mL quantitative flask, toluene (230 g) and acetyl chloride (41.6 g, 0.53 mol) were added, stirred, and dissolved. The solution was then stored separately. To a 1 L reaction flask, toluene (140 g), 40 wt% aqueous sodium hydroxide solution (140 g, 1.4 mol), and 2-(4-trifluoromethyl)phenethyl alcohol (95 g, 0.5 mol) were added and cooled to 0-10°C. The toluene solution of acetyl chloride was then added dropwise. The reaction was then carried out at 20-25°C for 8 hours and monitored by GC. After the reaction was complete, drinking water was added and the mixture was stirred for layer separation. The organic phase was concentrated under reduced pressure to obtain the concentrated crude product. The temperature was raised to 50-60°C, and a mixed solvent of ethyl acetate and n-heptane (150 g) was added dropwise. Next, the mixture was cooled to 20-25°C, crystallized, filtered by suction, and dried to obtain a dried product (93 g, 0.4 mol) of the target compound with 98% HPLC purity and 80% yield.

[0105] (2) Methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoate hemisulfate:

[0106] [ka]

[0107] 46.4 g, 0.20 mol, 2-(4-trifluoromethyl)phenethyl acetate, 35 g, 0.21 mol, toluene, and 24 g, 0.24 mol, triethylamine were added to a 1 L reaction flask. The mixture was heated and maintained at 90-100°C for 12 hours. After sampling and testing were completed, the reaction was stopped. Drinking water was then added and the mixture was stirred for layer separation. The organic phase was concentrated under reduced pressure until the distillate was gone. 168 g, methanol, was added and stirred to dissolve it. The mixture was heated to 35-40°C, and 23 g, 0.12 mol, 50 wt%, aqueous sulfuric acid solution was added dropwise. Next, the mixture was stirred for 15 minutes, gradually cooled to 25-30°C, and then subjected to adiabatic crystallization over 1 hour, followed by suction filtration and drying to obtain hemisulfate of compound III (60 g, 0.15 mol) with 98.5% HPLC purity and 77% yield.

[0108] (3) Production of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid: 240 g of 40 wt% aqueous sulfuric acid, 80 g of glacial acetic acid, and 60 g of hemisulfate of compound III were added to a 500 mL reaction flask. The temperature was raised to 80-85°C while nitrogen was added to the reaction solution, and the bubbling reaction was carried out over 4 hours. After sample collection and testing were completed, activated carbon was added for decolorization, and the solution was filtered. The filtrate was gradually cooled to -5-5°C, held for 1 hour, filtered by suction, and dried to obtain 40 g of dried compound IV with an HPLC purity of 99.639%, a content of divalently substituted impurities of 0.128%, and a content of meta-isomer impurities of 0.097% (shown in Figure 3), with a yield of 82%.

[0109] Example 4: (1) Preparation of 2-(4-trifluoromethyl)phenethyltrifluoromethanesulfonate:

[0110] [ka]

[0111] To a 500 mL quantitative flask, toluene (230 g) and trifluoromethanesulfonic anhydride (150 g, 0.53 mol) were added, stirred, and dissolved. The solution was then stored separately. To a 1 L reaction flask, toluene (140 g), triethylamine (64 g, 0.63 mol), and 2-(4-trifluoromethyl)phenethyl alcohol (95 g, 0.5 mol) were added and cooled to 0-10°C. Next, the toluene solution of trifluoromethanesulfonic anhydride was added dropwise. The reaction was then carried out at 20-25°C for 8 hours and monitored by GC. After the reaction was complete, drinking water was added and the mixture was stirred for layer separation. The organic phase was concentrated under reduced pressure to obtain the concentrated crude product. The temperature was raised to 50-60°C, and a mixed solvent of ethyl acetate and n-heptane (150 g) was added dropwise. Next, the mixture was cooled to 20-25°C, crystallized, filtered by suction, and dried to obtain a dried product (129 g, 0.4 mol) of the target compound with 98.5% HPLC purity and 80% yield.

[0112] (2) Preparation of methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoate hemisulfate:

[0113] [ka]

[0114] 64.5 g, 0.20 mol, 2-(4-trifluoromethyl)phenethyltrifluoromethanesulfonate, 35 g, 0.21 mol, toluene, and 24 g, 0.24 mol, triethylamine were added to a 1 L reaction flask. The mixture was heated and maintained at 90-100°C for 12 hours. After sampling and testing were completed, the reaction was stopped. Drinking water was then added and the mixture was stirred for layer separation. The organic phase was concentrated under reduced pressure until the distillate was gone. 168 g, methanol, was added and stirred to dissolve it. The mixture was heated to 35-40°C, and 23 g, 0.12 mol, 50 wt%, aqueous sulfuric acid solution was added dropwise. Next, the mixture was stirred for 15 minutes, gradually cooled to 25-30°C, and then subjected to adiabatic crystallization over 1 hour, followed by suction filtration and drying to obtain hemisulfate (61 g) of compound III with 98.5% HPLC purity and a yield of 78.3%.

[0115] (3) Production of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid: 240 g of 40 wt% aqueous sulfuric acid, 80 g of glacial acetic acid, and 60 g of hemisulfate of compound III were added to a 500 mL reaction flask. The temperature was raised to 80-85°C while nitrogen was added to the reaction solution, and the bubbling reaction was carried out over 4 hours. After sample collection and testing were completed, activated carbon was added for decolorization and the solution was filtered. The filtrate was gradually cooled to -5-5°C, held for 1 hour, filtered by suction, and dried to obtain a dried product (40.5 g) of compound IV with an HPLC purity of 99.762%, a content of divalently substituted impurities of 0.023%, and a content of meta-isomer impurities of 0.068% (shown in Figure 4), with a yield of 83%.

[0116] Comparative example: (1) Preparation of 2-(4-trifluoromethyl)phenethylmethylsulfonate:

[0117] [ka]

[0118] To a 500 mL quantitative flask, toluene (230 g) and methylsulfonyl chloride (60 g, 0.53 mol) were added, stirred, and dissolved. The solution was then stored separately. To a 1 L reaction flask, toluene (140 g), 40 wt% aqueous sodium hydroxide solution (140 g, 1.4 mol), and 2-(4-trifluoromethyl)phenethyl alcohol (95 g, 0.5 mol) were added and cooled to 0-10°C. The toluene solution of methylsulfonyl chloride was then added dropwise. The reaction was then carried out at 20-25°C for 10 hours and monitored by GC. After the reaction was complete, drinking water was added and the mixture was stirred for phase separation. The organic phase was concentrated under reduced pressure, and then n-hexane (200 g) was added. Next, the mixture was cooled to -10 to 0°C, crystallized, filtered by suction, and dried under vacuum at 0 to 10°C to obtain a dried product (116 g, 0.43 mol) of the target compound with 97% HPLC purity and 0.3% meta-isomer content, with a yield of 86%.

[0119] (2) Preparation of methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoate hemisulfate:

[0120] [ka]

[0121] 53.6 g, 0.20 mol, 2-(4-trifluoromethyl)phenethylmethylsulfonate, 35 g, 0.21 mol, toluene, and triethylamine were added to a 1 L reaction flask. The mixture was heated and maintained at 80-90°C for 18 hours. After sampling and testing were completed, the reaction was stopped. Drinking water was then added and the mixture was stirred for layer separation. The organic phase was concentrated under reduced pressure until the distillate was gone. 160 g of methanol was added and stirred to dissolve it. The mixture was heated to 35-40°C, and 23 g, 0.12 mol, 50 wt%, aqueous sulfuric acid solution was added dropwise. Next, the mixture was stirred for 15 minutes, gradually cooled to 25-30°C, and then subjected to adiabatic crystallization over 1 hour, followed by suction filtration and drying to obtain hemisulfate (57 g) of compound III with an HPLC purity of 97.3%, a meta-isomer content of 0.24%, and a divalently substituted impurity content of 1.8%, with a yield of 73%.

[0122] (3) Production of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid: 300 g of 40% aqueous sulfuric acid, 100 g of glacial acetic acid, and 77 g of compound III were added to a 500 mL reaction flask. The temperature was raised to 80-95°C and maintained for 24 hours. After sample collection and testing were completed, activated carbon was added for decolorization and the mixture was filtered. The filtrate was gradually cooled to -5-5°C and maintained for 1 hour, then filtered by suction and dried to obtain a dried product (52 g) of compound IV with an HPLC purity of 99.388%, a content of divalently substituted impurities of 0.285%, and a content of meta-isomer impurities of 0.155% (shown in Figure 5), with a yield of 81%.

[0123] In Example 1 described above, by using p-methylbenzenesulfonyl chloride as a protecting reagent (i.e., using p-methylbenzenesulfonyl as a protecting group), no divalently substituted impurities or meta-isomer impurities were detected in the final product, and therefore, 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid was obtained with a very high purity of 99.957% and a high yield of 93%.

[0124] In Example 2 described above, by using benzenesulfonyl chloride as a protecting reagent (i.e., using benzenesulfonyl as a protecting group), divalently substituted impurities and meta-isomer impurities were detected in the final product at a content of at most less than 0.04%, and thus 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid was obtained with a high purity of 99.831% and a high yield of 91%.

[0125] In Example 3 described above, by using acetyl chloride as a protecting reagent (i.e., using acetyl as a protecting group), divalently substituted impurities and meta-isomer impurities were detected in the final product at a content of at most less than 0.13%, and thus 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid was obtained with a high purity of 99.639% and a yield of 82%.

[0126] In Example 4 described above, by using trifluoromethanesulfonic anhydride as a protecting reagent (i.e., using trifluoromethanesulfonyl as a protecting group), divalently substituted impurities and meta-isomer impurities were detected in the final product at a content of at most less than 0.07%, and thus 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid was obtained with a high purity of 99.762% and a yield of 83%.

[0127] However, in the comparative example, methylsulfonyl chloride was used as a protective reagent, resulting in the formation of a low-stability intermediate, 2-(4-trifluoromethyl)phenethylmethylsulfonate. The final product produced had a content of 0.285% divalently substituted impurities, a content of 0.155% meta-isomer impurities, a purity of at best 99.388%, and a yield of at best 81%.

[0128] As is clear from the above comparison, by using specific protective reagents, the present invention effectively controls divalently substituted and isomeric impurities of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid in the final product, significantly improving the quality of the product and also greatly improving the reaction yield.

[0129] Although the present invention has been described above with reference to specific embodiments, the scope of protection of the present invention is not limited in any way to these embodiments. Any modification or equivalent substitution that does not depart from the concept of the present invention is included within the scope of protection of the present invention.

Claims

1. A method for producing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid, including the following steps: 1) A step of obtaining compound II by reacting compound I with a protective reagent, 【Chemistry 1】 2) The step of obtaining compound III by condensing compound II with methyl 5-aminosalicylate, 【Chemistry 2】 3) A step of hydrolyzing compound III to obtain the target compound IV. 【Transformation 3】 Here, R is one of the following: p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, and acetyl.

2. The method according to claim 1, wherein the protective reaction is carried out at a temperature of 0 to 30°C.

3. The method according to claim 1, wherein the protective reaction is carried out in a solvent, the solvent being at least one of toluene, ethylbenzene, xylene, methylene chloride, and chloroform.

4. The method according to claim 1, further comprising step 1) purifying crude compound II.

5. The aforementioned purification is carried out by crystallization, which is performed by dissolution at 40-80°C and adiabatic crystallization at 0-40°C. The method according to claim 4, wherein the solvent used for the crystallization is at least one of ethyl acetate, n-hexane, n-heptane, toluene, methylene chloride, methanol, ethanol, isopropanol, and water.

6. The method according to claim 1, wherein the condensation reaction is carried out at a temperature of 30 to 100°C.

7. The method according to claim 1, wherein the condensation reaction is carried out in a solvent, and the solvent is at least one of toluene, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran.

8. The method according to claim 1, wherein the condensation reaction is carried out in the presence of a base, the base being at least one of triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, and pyridine.

9. The method according to claim 1, further comprising step 2) forming a salt of crude compound III using an acid or an aqueous solution thereof.

10. The salt formation is carried out using an inorganic acid, the inorganic acid being at least one of hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, according to claim 9.

11. The method according to claim 1, wherein the hydrolysis reaction is carried out at a temperature of 60 to 100°C.

12. The method according to claim 1, wherein the hydrolysis reaction is carried out in the presence of an acid, which is sulfuric acid.

13. The method according to claim 1, wherein the hydrolysis reaction is carried out by nitrogen bubbling.

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