METHOD FOR PREPARING 2-HYDROXY-5-[2-(4-(TRIFLUOROMETHYLPHENYL)ETHYLAMINO)]BENZOIC ACID

Abstract

A method for preparing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid is proposed. The method may include protection, condensation, and hydrolysis. By means of the screening of a hydroxyl protecting reagent for a starting material, for example, 2-(4-trifluoromethyl)phenethylalcohol and the optimization of other process parameters, the contents of meta-isomer impurities and disubstituted impurities in a target product are effectively controlled. Accordingly, the quality of the product is significantly improved, the reaction yield is also greatly improved, and the improved product quality can satisfy related requirements of preparation research.

Claims

1. A method for preparing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid, the method comprising: subjecting Compound I to a protection reaction with a protective reagent to obtain Compound II, wherein the Compound I and the Compound II are respectively represented as I and II below, ##STR00018## subjecting the Compound II to a condensation reaction with methyl 5-aminosalicylate to obtain Compound III, wherein the Compound III is represented as III below, ##STR00019## subjecting the Compound III to a hydrolysis reaction to obtain a target Compound IV, wherein the target Compound IV is represented as IV below, ##STR00020## wherein R is any one of p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl, or acetyl.

2. The method according to claim 1, wherein: the protection reaction is carried out at a temperature of 0-30 C., or 20-25 C.

3. The method according to claim 1, wherein: the protection reaction is carried out in a solvent, which comprises at least one of toluene, ethylbenzene, xylene, methylene chloride, or chloroform.

4. The method according to claim 1, wherein: subjecting the Compound I further comprises refining the crude Compound II.

5. The method according to claim 4, wherein: the refining is done by crystallization, which is performed by dissolving at a temperature of 40-80 C. and insulation crystallizing at a temperature of 0-40 C., or dissolving at a temperature of 50-60 C. and insulation crystallizing at a temperature of 20-30 C., and the solvent used for the crystallization comprises at least one of ethyl acetate, n-hexane, n-heptane, toluene, methylene chloride, methanol, ethanol, isopropanol, or water.

6. The method according to claim 1, wherein: the condensation reaction is carried out at a temperature of 30-100 C., or 80-90 C.

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

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

9. The method according to claim 1, wherein: subjecting the Compound II further comprises forming a salt of a crude Compound III using an acid or an aqueous solution thereof.

10. The method according to claim 9, wherein: the salt-forming is performed by using an inorganic acid, which comprises any one of hydrochloric acid, sulfuric acid, nitric acid, or phosphoric acid.

11. The method according to claim 1, wherein: the hydrolysis reaction is carried out at a temperature of 60-100 C., or 80-85 C.

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

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

Description

DESCRIPTION OF DRAWINGS

[0026] FIG. 1 shows the HPLC chromatogram of the target product prepared in Example 1.

[0027] FIG. 2 shows the HPLC chromatogram of the target product prepared in Example 2.

[0028] FIG. 3 shows the HPLC chromatogram of the target product prepared in Example 3.

[0029] FIG. 4 shows the HPLC chromatogram of the target product prepared in Example 4.

[0030] FIG. 5 shows the HPLC chromatogram of the target product prepared in Comparative Example.

DETAILED EMBODIMENTS

[0031] The explanation of the technical features descried below is based on representative embodiments and specific examples of the present disclosure, but the present disclosure is not limited to these embodiments and specific examples.

[0032] Unless otherwise specified, the term compound as used in the present disclosure includes all stereoisomeric forms, geometric isomeric forms, tautomeric forms and isotopically labeled forms of the compound.

[0033] Unless otherwise specified, the numerical range represented by numerical value A-numerical value B used in the present disclosure refers to a range comprising endpoint values A and B.

[0034] Unless otherwise specified, the numerical range represented by above or below used in the present disclosure refers to a numerical range including the number.

[0035] Unless otherwise specified, references in the present disclosure to some specific/preferred embodiments, other specific/preferred embodiments, embodiments and the like refer to that the particular elements (e.g., features, structures, properties and/or characteristics) described in connection with the embodiment are included in at least one of the embodiments described herein and may or may not be present in other embodiments. Further, it is to be understood that the elements can be combined in any suitable manners in various embodiments.

[0036] Unless otherwise specified, plurality as used in the present disclosure means that there are two or more of the item to which the term refers.

[0037] Hereinafter, the present disclosure will be described in detail.

[0038] The present disclosure provides a method for preparing 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid with high yield and purity.

[0039] The method comprises steps of: [0040] (1) subjecting Compound I to a protection reaction with a protective reagent to obtain Compound II,

##STR00004## [0041] (2) subjecting Compound II to a condensation reaction with methyl 5-aminosalicylate to obtain Compound III,

##STR00005## [0042] (3) subjecting Compound III to a hydrolysis reaction to obtain the target Compound IV, which is 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid,

##STR00006##

[0043] wherein, R is any one of p-methylbenzenesulfonyl, p-nitrobenzenesulfonyl, benzenesulfonyl, trifluoromethanesulfonyl and acetyl, preferably p-methylbenzenesulfonyl or benzenesulfonyl, more preferably p-methylbenzenesulfonyl.

[0044] Step (1)

[0045] Step (1) is a step of subjecting Compound I (i.e., 2-(4-trifluoromethyl)phenethyl alcohol) to a protection reaction with a protective reagent to obtain Compound II (i.e., 2-(4-trifluoromethyl)phenethyl sulfonate or carboxylate).

[0046] In step (1), the selection of the protective group plays a key role in the removal of meta-isomer impurities in this step and the control of the disubstituted impurities in step (2).

[0047] In an embodiment of the present disclosure, the protective 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 their corresponding anhydrides. Accordingly, the protecive group (i.e., group R) in Compound II may be any one of p-methylbenzenesulfonyl, trifluoromethanesulfonyl, acetyl, benzenesulfonyl and p-nitrophenylsulfonyl.

[0048] In a preferred embodiment of the present disclosure, the protecting reagent used to protect Compound I in step (1) may be p-methylbenzenesulfonyl chloride or benzenesulfonyl chloride.

[0049] In a more preferred embodiment of the present disclosure, the protecting reagent used to protect compound I in step (1) may be p-methylbenzenesulfonyl chloride.

[0050] The intermediate 2-(4-trifluoromethyl)phenethyl methanesulfonate used in the prior art has poor stability, low melting point, and is not easy to refine and purify. In particular, the isomer impurities are difficult to remove, and the content of the disubstituted impurities in the condensation reaction is high, thereby affecting the quality of the final product. In contrast, by using the above-mentioned protective reagents, the intermediates obtained by the present disclosure are 2-(4-trifluoromethyl)phenethyl p-methylbenzenesulfonate, 2-(4-trifluoromethyl)phenethyl trifluoromethanesulfonate, 2-(4-trifluoromethyl)phenethyl acetate, 2-(4 -trifluoromethyl)phenethyl benzenesulfonate and 2-(4-trifluoromethyl)phenethyl p-nitrobenzenesulfonate, respectively, which overcome the above-mentioned shortcomings of 2-(4-trifluoromethyl)phenethyl methanesulfonate. As a result, a final product 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid can be prepared with high purity and yield.

[0051] In an embodiment of the present disclosure, the protection reaction in step (1) is carried out at low temperature.

[0052] In a preferred embodiment of the present disclosure, the protection reaction in step (1) is carried out at 0-30 C.

[0053] In a preferred embodiment of the present disclosure, the protection reaction in step (1) is carried out at 20-25 C.

[0054] In an embodiment of the present disclosure, the protection reaction in step (1) may be carried out in a solvent.

[0055] In a preferred embodiment of the present disclosure, the protection reaction in step (1) may be carried out in an organic solvent, which may be at least one of toluene, ethylbenzene, xylene, methylene chloride and chloroform.

[0056] In a preferred embodiment of the present disclosure, the protection reaction in step (1) may be carried out in toluene.

[0057] After the protection reaction in step (1) is completed, water may be added to the system, and stirred for layer separation, and then the separated organic phase may be concentrated under reduced pressure to obtain a crude Compound II, which is further refined in order to obtain a Compound II with high purity.

[0058] In an embodiment of the present disclosure, step (1) may further comprise a step of refining the crude Compound II. Generally, the refining step can be done by means of crystallization. And, the selection of the solvent used for the crystallization has a great influence on the removal of meta-isomers in step (1).

[0059] In a preferred embodiment of the present disclosure, the solvent used for the crystallization may be at least one of ethyl acetate, n-hexane, n-heptane, toluene, methylene chloride, methanol, ethanol, isopropanol and water.

[0060] In a more preferred embodiment of the present disclosure, the solvent used for the crystallization may be n-heptane.

[0061] In addition, when refining the crude Compound II by means of crystallization, the temperature of the crystallization can also be controlled to facilitate the removal of the impurities and the precipitation of the target product. If the temperature of the crystallization is too high, the yield will be affected, and if it is too low, the purity of Compound II will be reduced.

[0062] In an embodiment of the present disclosure, the crystallization may be performed by dissolving at 40-80 C. and insulation crystallizing at 0-40 C.

[0063] In a preferred embodiment of the present disclosure, the crystallisation may be performed by dissolving at 50-60 C. and insulation crystallizing at 20-30 C.

[0064] Step (2)

[0065] Step (2) is a step of subjecting Compound II to a condensation reaction with methyl 5-aminosalicylate to obtain Compound III (i.e., methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl) ethylamino)]benzoate).

[0066] In step (2), the reaction temperature has a great influence on the disubstituted impurities, and an increase in temperature will lead to a significant increase in the content of the disubstituted impurities.

[0067] In an embodiment of the present disclosure, the condensation reaction in step (2) may be carried out at a temperature of 30-100 C.

[0068] In a preferred embodiment of the present disclosure, the condensation reaction in step (2) may be carried out at a temperature of 80-90 C.

[0069] In an embodiment of the present disclosure, the condensation reaction in step (2) may be carried out in a solvent.

[0070] In a preferred embodiment of the present disclosure, the condensation reaction in step (2) may be carried out in an organic solvent, which may be at least one of toluene, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide and tetrahydrofuran.

[0071] In a more preferred embodiment of the present disclosure, the condensation reaction in step (2) may be carried out in toluene.

[0072] In an embodiment of the present disclosure, the condensation reaction in step (2) may be carried out in the presence of a base, which may be at least one of triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and pyridine.

[0073] In an embodiment of the present disclosure, the condensation reaction in step (2) may be carried out in the presence of triethylamine.

[0074] After the condensation reaction in step (2) is completed, water may be added to the system, and stirred for layer separation, and then the separated organic phase may be concentrated under reduced pressure to obtain a crude Compound III.

[0075] Since the crude Compound III is usually difficult to exist in solid form and cannot be directly crystallized, it needs to be converted into a salt form, which will be beneficial to obtain a solid, and achieve the purpose of separation and purification through crystallization.

[0076] In an embodiment of the present disclosure, step (2) further comprises a step of forming a salt of the crude Compound III using an acid (or a solution, preferably an aqueous solution thereof). Generally, the salt-forming step can be performed by using an inorganic or organic acid. Common inorganic acids include (but not limited to) hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid. Common organic acids include (but not limited to) acetic acid, lactic acid, citric acid, malic acid and tartaric acid.

[0077] In a preferred embodiment of the present disclosure, the acid used for the salt-forming may be any one of hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, or an aqueous solution of any concentration thereof.

[0078] In a more preferred embodiment of the present disclosure, the acid used for the salt-forming may be sulfuric acid, or an aqueous solution of any concentration thereof.

[0079] Accordingly, when the acid used for the salt-forming is sulfuric acid, the acid addition salt of Compound III is preferably a hemisulfate.

[0080] Step (3)

[0081] Step (3) is a step of subjecting Compound III (i.e., methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoate) or an acid addition salt (such as hemisulfate) thereof to a hydrolysis reaction to obtain the target Compound IV (i.e., 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid).

[0082] In an embodiment of the present disclosure, the hydrolysis reaction in step (3) may be carried out at a temperature of 60-100 C.

[0083] In a preferred embodiment of the present disclosure, the hydrolysis reaction in step (3) may be carried out at a temperature of 80-85 C.

[0084] In an embodiment of the present disclosure, the hydrolysis reaction in step (3) may be carried out in the presence of acid, which may be sulfuric acid, or an aqueous solution of any concentration thereof.

[0085] In an embodiment of the present disclosure, the acid used for hydrolysis may be sulfuric acid.

[0086] In order to make the prepared Compound IV have higher purity, activated carbon may further be added for decolorization.

[0087] In an embodiment of the present disclosure, the hydrolysis reaction in step (3) may be carried out with nitrogen bubbling, which can obviously shorten the reaction time and improve the reaction conversion rate.

[0088] In addition, it should be particularly noted that, unless otherwise defined, each step in the preparation method of the present disclosure detects the endpoint of the reaction by HPLC method; the reaction raw materials are generally reacted according to the chemical reaction stoichiometry ratio or in excess; the amount of reaction solvent and/or catalyst can be adjusted according to the amount of the reaction raw materials, specifically, it can be increased with more reaction raw materials, and decreased with less reaction raw materials.

[0089] For a better understanding of the technical solutions of the present disclosure, it is further described below in connection with specific examples, but those of ordinary skill in the art should recognize that the present disclosure is not limited to these examples.

EXAMPLE 1

(1) Preparation of 2-(4-trifluoromethyl)phenethyl p-methylbenzenesulfonate

[0090] ##STR00007##

[0091] In a 500 mL volumetric flask, toluene (230 g) and p-methylbenzenesulfonyl chloride (100 g, 0.53 mol) were added, stirred to dissolve, and set aside. In a 1 L reaction flask, toluene (140 g), 40 wt % of sodium hydroxide aqueous solution (140 g, 1.4 mol), and 2-(4-trifluoromethyl)phenethyl alcohol (95 g, 0.5 mol) were added, and cooled down to 0-10 C. Then a toluene solution of p-methylbenzenesulfonyl chloride was added dropwise. Thereafter, it was reacted at 20-25 C. for 6 hours and monitored by GC. After the reaction was completed, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure to obtain a concentrated crude product. The temperature was raised to 50-60 C., and n-heptane (170 g) was added dropwise. Thereafter, it was cooled down to 20-25 C., crystallized, suction filtered, and dried to obtain a dry product of the target compound (163 g), with a HPLC purity of 99.6%, a content of meta-isomer impurities of 0.03%, and a yield of 95%.

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

[0092] ##STR00008##

[0093] In a 1 L reaction flask, 2-(4-trifluoromethyl)phenethyl p-methylbenzenesulfonate (68 g, 0.20 mol), methyl 5-aminosalicylate (35 g, 0.21 mol), toluene (200 g), and triethylamine (24 g, 0.24 mol) were added. It was heated to and kept at 80-10 C., and reacted for 14 hours. The reaction was stopped after sampling and passing the test. Thereafter, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure until there was no distillate. Methanol (160 g) was added thereto, stirred to dissolve, and heated to 35-40 C., and 50 wt % of sulfuric acid aqueous solution (23 g, 0.12 mol) was added dropwise. Thereafter, it was stirred for 15 minutes, cooled down slowly to 25-30 C., insulation crystallized for 1 hour, suction filtered, and dried to obtain a hemisulfate of Compound III (67 g, 0.17 mol), with a HPLC purity of 99% and a yield of 86.3%.

(3) Preparation of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid

[0094] ##STR00009##

[0095] In a 500 mL reaction flask, 40 wt % of sulfuric acid aqueous solution (300 g), glacial acetic acid (100 g) and the hemisulfate of Compound III (77 g) were added. The temperature was raised to 80-85 C., while nitrogen was introduced into the reaction solution, and the bubbling reaction was carried out for 4 hours. After sampling and passing the test, activated carbon was added for decolorization, and filtered. The filtrate was slowly cooled down to 5 to 5 C., kept for 1 hour, suction filtered, and dried to obtain a dry product of Compound IV (58.4 g), with a HPLC purity of 99.957% and a yield of 93%. The disubstituted impurities and meta-isomer impurities were not detected (as shown in FIG. 1).

EXAMPLE 2

(1) Preparation of 2-(4-trifluoromethyl)phenethyl benzenesulfonate

[0096] ##STR00010##

[0097] In a 500 mL volumetric flask, toluene (230 g) and benzenesulfonyl chloride (93 g, 0.53 mol) were added, stirred to dissolve, and set aside. In a 1 L reaction flask, toluene (140 g), 40 wt % of sodium hydroxide aqueous solution (140 g, 1.4 mol), and 2-(4-trifluoromethyl)phenethyl alcohol (95 g, 0.5 mol) were added, and cooled down to 0-10 C. Then a toluene solution of benzenesulfonyl chloride was added dropwise. Thereafter, it was reacted at 20-25 C. for 8 hours and monitored by GC. After the reaction was completed, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure to obtain a 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. Thereafter, it was cooled down to 20-25 C., crystallized, suction filtered, and dried to obtain a dry product of the target compound (145 g, 0.44 mol), with a HPLC purity of 98% and a yield of 89%.

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

[0098] ##STR00011##

[0099] In a 1 L reaction flask, 2-(4-trifluoromethyl)phenethyl benzenesulfonate (66 g, 0.20 mol), methyl 5-aminosalicylate (35 g, 0.21 mol), toluene (200 g), and 24 g of triethylamine (24 g, 0.24 mol) were added. It was heated to and kept at 90-100 C., and reacted for 12 hours. The reaction was stopped after sampling and passing the test. Thereafter, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure until there was no distillate. Methanol (168 g) was added thereto, stirred to dissolve, and heated to 35-40 C., and 50 wt % of sulfuric acid aqueous solution (23 g, 0.12 mol) was added dropwise. Thereafter, it was stirred for 15 minutes, cooled down slowly to 25-30 C., insulation crystallized for 1 hour, suction filtered, and dried to obtain a hemisulfate of Compound III (62 g), with a HPLC purity of 98.5% and a yield of 80%.

(3) Preparation of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid

[0100] In a 500 mL reaction flask, 40 wt % of sulfuric acid aqueous solution (240 g), glacial acetic acid (80 g) and the hemisulfate of Compound III (60 g) were added. The temperature was raised to 80-85 C., while nitrogen was introduced into the reaction solution, and the bubbling reaction was carried out for 4 hours. After sampling and passing the test, activated carbon was added for decolorization, and filtered. The filtrate was slowly cooled down to 5 to 5 C., kept for 1 hour, suction filtered, and dried to obtain a dry product, of Compound IV (44.5 g), with a HPLC purity of 99.831%, a content of disubstituted impurities of 0.025%, a content of meta-isomer impurities of 0.033% (as shown in FIG. 2), and a yield of 91%.

EXAMPLE 3

(1) Preparation of 2-(4-trifluoromethyl)phenethyl acetate

[0101] ##STR00012##

[0102] In a 500 mL volumetric flask, toluene (230 g) and acetyl chloride (41.6 g, 0.53 mol) were added, stirred to dissolve, and set aside. In a 1 L reaction flask, toluene (140 g), 40 wt % of sodium hydroxide aqueous solution (140 g, 1.4 mol), and 2-(4-trifluoromethyl)phenethyl alcohol (95 g, 0.5 mol) were added, and cooled down to 0-10 C. Then a toluene solution of acetyl chloride was added dropwise. Thereafter, it was reacted at 20-25 C. for 8 hours and monitored by GC. After the reaction was completed, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure to obtain a 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. Thereafter, it was cooled down to 20-25 C., crystallized, suction filtered, and dried to obtain a dry product of the target compound (93 g, 0.4 mol), with a HPLC purity of 98% and a yield of 80%.

(2) Preparation of Methyl 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoate hemisulfate

[0103] ##STR00013##

[0104] In a 1 L reaction flask, 2-(4-trifluoromethyl)phenethyl acetate (46.4 g, 0.20 mol), methyl 5-aminosalicylate (35 g, 0.21 mol), toluene (200 g), and 24 g of triethylamine (24 g, 0.24 mol) were added. It was heated to and kept at 90-100 C., and reacted for 12 hours. The reaction was stopped after sampling and passing the test. Thereafter, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure until there was no distillate. Methanol (168 g) was added thereto, stirred to dissolve, and heated to 35-40 C., and 50 wt % of sulfuric acid aqueous solution (23 g, 0.12 mol) was added dropwise. Thereafter, it was stirred for 15 minutes, cooled down slowly to 25-30 C., insulation crystallized for 1 hour, suction filtered, and dried to obtain a hemisulfate of Compound III (60 g, 0.15 mol), with a HPLC purity of 98.5% and a yield of 77%.

(3) Preparation of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid

[0105] In a 500 mL reaction flask, 40 wt % of sulfuric acid aqueous solution (240 g), glacial acetic acid (80 g) and the hemisulfate of Compound III (60 g) were added. The temperature was raised to 80-85 C., while nitrogen was introduced into the reaction solution, and the bubbling reaction was carried out for 4 hours. After sampling and passing the test, activated carbon was added for decolorization, and filtered. The filtrate was slowly cooled down to 5 to 5 C., kept for 1 hour, suction filtered, and dried to obtain a dry product of Compound IV (40 g), with a HPLC purity of 99.639%, a content of disubstituted impurities of 0.128%, a content of meta-isomer impurities of 0.097% (as shown in FIG. 3), and a yield of 82%.

EXAMPLE 4

(1) Preparation of 2-(4-trifluoromethyl)phenethyl trifluoromethanesulfonate

[0106] ##STR00014##

[0107] In a 500 mL volumetric flask, toluene (230 g) and trifluoromethanesulfonic anhydride (150 g, 0.53 mol) were added, stirred to dissolve, and set aside. In 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 down to 0-10 C. Then a toluene solution of trifluoromethanesulfonic anhydride was added dropwise. Thereafter, it was reacted at 20-25 C. for 8 hours and monitored by GC. After the reaction was completed, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure to obtain a 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. Thereafter, it was cooled down to 20-25 C., crystallized, suction filtered, and dried to obtain a dry product of the target compound (129 g, 0.4 mol), with a HPLC purity of 98.5% and a yield of 80%.

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

[0108] ##STR00015##

[0109] In a 1 L reaction flask, 2-(4-trifluoromethyl)phenethyl trifluoromethanesulfonate (64.5 g, 0.20 mol), methyl 5-aminosalicylate (35 g, 0.21 mol), toluene (200 g), and 24 g of triethylamine (24 g, 0.24 mol) were added. It was heated to and kept at 90-100 C., and reacted for 12 hours. The reaction was stopped after sampling and passing the test. Thereafter, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure until there was no distillate. Methanol (168 g) was added thereto, stirred to dissolve, and heated to 35-40 C. and 50 wt % of sulfuric acid aqueous solution (23 g, 0.12 mol) was added dropwise. Thereafter, it was stirred for 15 minutes, cooled down slowly to 25-30 C., insulation crystallized for 1 hour, suction filtered, and dried to obtain a hemisulfate of Compound III (61 g), with a HPLC purity of 98.5% and a yield of 78.3%.

(3) Preparation of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid

[0110] In a 500 mL reaction flask, 40 wt % of sulfuric acid aqueous solution (240 g), glacial acetic acid (80 g) and the hemisulfate of Compound III (60 g) were added. The temperature was raised to 80-85 C., while nitrogen was introduced into the reaction solution, and the bubbling reaction was carried out for 4 hours. After sampling and passing the test, activated carbon was added for decolorization, and filtered. The filtrate was slowly cooled down to 5 to 5 C., kept for 1 hour, suction filtered, and dried to obtain a dry product of Compound IV (40.5 g), with a HPLC purity of 99.762%, a content of disubstituted impurities of 0.023%, a content of meta-isomer impurities of 0.068% (as shown in FIG. 4), and a yield of 83%.

COMPARATIVE EXAMPLE

(1) Preparation of 2-(4-trifluoromethyl)phenethyl methylsulfonate

[0111] ##STR00016##

[0112] In a 500 mL volumetric flask, toluene (230 g) and methylsulfonyl chloride (60 g, 0.53 mol) were added, stirred to dissolve, and set aside. In a 1 L reaction flask, toluene (140 g), 40 wt % of sodium hydroxide aqueous solution (140 g, 1.4 mol), and 2-(4-trifluoromethyl)phenethyl alcohol (95 g, 0.5 mol) were added, and cooled down to 0-10 C. Then a toluene solution of methylsulfonyl chloride was added dropwise. Thereafter, it was reacted at 20-25 C. for 10 hours and monitored by GC. After the reaction was completed, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure, then n-hexane (200 g) was added. Thereafter, it was cooled down to 10 to 0 C., crystallized, suction filtered, and dried under vacuum at 0-10 C. to obtain a dry product of the target compound (116 g, 0.43 mol), with a HPLC purity of 97%, a content of meta-isomers of 0.3%, and a yield of 86%.

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

[0113] ##STR00017##

[0114] In a 1 L reaction flask, 2-(4-trifluoromethyl)phenethyl methylsulfonate (53.6 g, 0.20 mol), methyl 5-aminosalicylate (35 g, 0.21 mol), toluene (200 g), and triethylamine (24 g, 0.24 mol) were added. It was heated to and kept at 80-90 C., and reacted for 18 hours. The reaction was stopped after sampling and passing the test. Thereafter, drinking water was added, and stirred for layer separation. The organic phase was concentrated under reduced pressure until there was no distillate. Methanol (160 g) was added thereto, stirred to dissolve, and heated to 35-40 C., and 50 wt % of sulfuric acid aqueous solution (23 g, 0.12 mol) was added dropwise. Thereafter, it was stirred for 15 minutes, cooled down slowly to 25-30 C., insulation crystallized for 1 hour, suction filtered, and dried to obtain a hemisulfate of Compound III (57 g), with a HPLC purity of 97.3%, a content of meta-isomers of 0.24%, a content of disubstituted impurities of 1.8%, and a yield of 73%.

(3) Preparation of 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid

[0115] In a 500 mL reaction flask, 40% of sulfuric acid aqueous solution (300 g), glacial acetic acid (100 g) and Compound III (77 g) were added. The temperature was raised to 80-95 C. and kept for 24 hours. After sampling and passing the test, activated carbon was added for decolorization, and filtered. The filtrate was slowly cooled down to 5 to 5 C., kept for 1 hour, suction filtered, and dried to obtain a dry product of Compound IV (52 g), with a HPLC purity of 99.388%, a content of disubstituted impurities of 0.285%, a content of meta-isomer impurities of 0.155% (as shown in FIG. 5), and a yield of 81%.

[0116] In the above Example 1, by using p-methylbenzenesulfonyl chloride as a protective reagent (i.e., using p-methylbenzenesulfonyl as a protecive group), the disubstituted impurities and meta-isomer impurities in the final product were not detected, and thus 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%.

[0117] In the above Example 2, by using benzenesulfonyl chloride as a protective reagent (i.e., using benzenesulfonyl as a protecive group), disubstituted impurities and meta-isomer impurities with a content only less than 0.04% were detected in the final product, and thus 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid was obtained with a high purity of 99.831% and a yield of 91%.

[0118] In the above Example 3, by using acetyl chloride as a protective reagent (i.e., using acetyl as a protecive group), disubstituted impurities and meta-isomer impurities with a content of only less than 0.13% were detected in the final product, 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%.

[0119] In the above Example 4, by using trifluoromethanesulfonic anhydride as a protective reagent (i.e., using trifluoromethanesulfonyl as a protecive group), disubstituted impurities and meta-isomer impurities with a content of only less than 0.07% were detected in the final product, 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%.

[0120] However, in the Comparative Example, due to the use of methylsulfonyl chloride as a protective reagent, an intermediate 2-(4-trifluoromethyl)phenethyl methylsulfonate with poor stability was formed, resulting in a final product with a content of disubstituted impunities of 0.285%, a content of meta-isomer impurities of 0.155%, a purity of only 99.388%, and a yield of only 81%.

[0121] As can be seen from the above comparison, by using specific protective reagents, the present disclosure effectively controls the isomer impurities and disubstituted impurities of the final product 2-hydroxy-5-[2-(4-(trifluoromethylphenyl)ethylamino)]benzoic acid, the product quality is significantly improved, and the reaction yield is also greatly improved.

[0122] While the present disclosure has been described above with respect to specific embodiments, the protection scope of the present, disclosure is not limited to these embodiments. All changes or equivalent substitutions that do not depart from the concept of the present disclosure are included within the protection scope of the present disclosure.