A process for the preparation of a linifexor intermediate, benzofuran-6-carboxylic acid

Abstract

The application discloses a preparation method of lifitegrast intermediate benzofuran-6-carboxylic acid, and relates to the technical field of medicines, and comprises the following steps: S1, ring-closing reaction of a compound of formula (I) with acetic anhydride under heating to obtain a compound of formula (II); S2, catalytic reaction of the compound of formula (II) with a compound of formula (III) under catalysis of n-butyl lithium to obtain a compound of formula (IV), and then first hydrolysis reaction under alkaline conditions to obtain benzofuran-6-carboxylic acid. The preparation method of the lifitegrast intermediate benzofuran-6-carboxylic acid is low in cost, high in yield and mild in reaction conditions.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and in particular to a method for preparing the leferistant intermediate benzofuran-6-carboxylic acid. Background Technology

[0002] Dry eye syndrome is a general term for a variety of diseases characterized by decreased tear film stability due to abnormalities in the quality and quantity of tears or tear dynamics caused by any reason, accompanied by eye discomfort and leading to ocular surface tissue lesions. It is a common ophthalmic disease. Mild dry eye syndrome can affect our work and daily life, while severe dry eye syndrome can lead to blindness. The pathogenesis of dry eye syndrome is complex and not yet fully understood. Dry eye syndrome is mainly classified into aqueous hypoplastic type, lipid abnormality type, mucin abnormality type, tear dynamics abnormality type, and dry eye syndrome caused by inflammation. Dry eye syndrome caused by inflammation is mainly mediated by neutrophils, through the activation of mitogen-activated protein kinase and nuclear factor-activated B cell K-light chain enhancement pathway, resulting in the production of inflammatory cytokines and thus inflammation.

[0003] Lifitegrast is an important drug for treating dry eye syndrome. It is a novel small-molecule integrin inhibitor that antagonizes lymphocyte function-associated antigen-1 (LFA-1) and blocks its interaction with its homologous ligand, intercellular adhesion molecule-1 (ICAM-1), thereby interfering with the overexpression of ICAM-1 in the corneal and conjunctival tissues that cause dry eye syndrome (Chen Benchuan. A new drug for treating dry eye syndrome—lifitegrast[J]. Medical Guide, 2017, 36(2):6). Benzofuran-6-carboxylic acid is a key intermediate in the preparation of lifitegrast.

[0004]

[0005] Existing literature discloses some methods for the synthesis of lefeldt or benzofuran-6-carboxylic acid:

[0006] Organic Syntheses (DOI:10.15227 / orgsyn.046.0028) has published a method for preparing benzofuran. Using salicylaldehyde as a starting material, benzofuran is obtained by substitution with chloroacetic acid followed by cyclization. The specific synthetic route is as follows:

[0007]

[0008] This method has a shorter route for preparing benzofuran, but the synthesis yield is low, with the highest yield of the second step being only 67.8%.

[0009] US Patent 16247843 discloses a method for preparing an LFA-1 inhibitor. The disclosed method for preparing benzofuran-6-carboxylic acid involves using 6-hydroxy-2H-benzofuran-3-one as a starting material, followed by reactions including tert-butyldimethylchlorosilane protection of hydroxyl groups, reduction, deprotection, and introduction of carboxyl groups to obtain benzofuran-6-carboxylic acid. The specific synthetic route is as follows:

[0010]

[0011] The disadvantages of this method are: first, the route is relatively complex; second, it requires the use of palladium acetate, which poses a risk of excessive heavy metal residues; third, it requires high pressure and the passage of carbon monoxide gas when introducing carboxyl groups, which is not conducive to safe production; and fourth, the reaction time is long.

[0012] Chinese patent CN110684000 discloses a preparation method using 3-hydroxybenzoic acid as a raw material, which involves introducing an aldehyde group with hexamethylenetetramine, esterification, witting reaction cyclization, and hydrolysis to obtain benzofuran-6-carboxylic acid. The specific synthetic route is as follows:

[0013]

[0014] The disadvantages of this method are: first, the reaction route is relatively long, and the overall yield is only 19.0%; second, hexamethylenetetramine is a controlled substance listed in the "List of Easily Explosive Hazardous Chemicals", and dibromomethane is a dangerous substance, making it inconvenient to purchase reagents; third, the high-temperature reaction time is more than 24 hours, which is not conducive to industrial production.

[0015] As can be seen, current methods for preparing the lefeldt intermediate benzofuran-6-carboxylic acid generally suffer from uneconomical drawbacks. The preparation process is complex, the initial raw materials are expensive, the reaction conditions are harsh, and the byproducts are difficult to control and remove. These problems will increase the synthesis cost of lefeldt, and there is an urgent need in the field for a lower-cost method for preparing benzofuran-6-carboxylic acid. Summary of the Invention

[0016] To address the aforementioned problems, this invention provides a method for preparing the leifester intermediate benzofuran-6-carboxylic acid, which is low-cost, high-yield, and has mild reaction conditions.

[0017] To achieve the above-mentioned objective, this invention provides a method for preparing the lefeld intermediate benzofuran-6-carboxylic acid, comprising the following steps:

[0018] S1, Compound (I) reacts with acetic anhydride under heating conditions to undergo a ring-closing reaction to obtain Compound (II);

[0019]

[0020] Where X is a halogen;

[0021] S2, Compound (II) and Compound (III) undergo a catalytic reaction under the catalysis of n-butyllithium to obtain Compound (IV), which then undergoes a first hydrolysis reaction under alkaline conditions to obtain benzofuran-6-carboxylic acid;

[0022]

[0023]

[0024] Where X is a halogen.

[0025] Preferably, in step S1, the heating temperature is 100–150°C, and the ring-closing reaction time is 5–12 h.

[0026] Preferably, in step S1, the mass ratio of the compound of formula (Ⅰ) to the volume ratio of acetic anhydride is 1:1 to 20.

[0027] Preferably, in step S2, the catalytic reaction is carried out under the protection of a protective gas, and the temperature of the catalytic reaction is -78 to -20°C; the molar ratio of compound (II) to compound (III) is 1:1.5 to 2.5.

[0028] Preferably, in step S2, the alkaline condition is pH ≥ 12;

[0029] Preferably, after the catalytic reaction is completed, an alkaline substance is added to the reaction solution to adjust the pH value, and the first hydrolysis reaction is carried out to obtain benzofuran-6-carboxylic acid.

[0030] Preferably, X in compound (I) and compound (II) is bromine, and X in compound (I) is chlorine.

[0031] Preferably, the method for preparing the compound of formula (I) includes the following steps:

[0032]

[0033] Where X is a halogen;

[0034] A1, Compound (V) reacts with a haloacetic acid ester under heating conditions to give compound (VI);

[0035] A2, compound (VI) undergoes a second hydrolysis under alkaline conditions to yield compound (I).

[0036] More preferably, the method for preparing the compound of formula (I) includes one or more of the following conditions:

[0037] (a) In step A1, the heating temperature is 40–100°C;

[0038] (b) In step A1, the haloacetic ester is selected from one or more of methyl chloroacetate, ethyl chloroacetate, benzyl chloroacetate, and isopropyl chloroacetate;

[0039] (c) In step A1, the molar ratio of compound (V) to haloacetic acid ester is 1:1 to 2;

[0040] (d) In step A1, the reaction time is 1 to 6 hours;

[0041] (e) In step A2, the alkaline condition is pH ≥ 12;

[0042] (f) In step A2, the compound of formula (VI) is mixed with an alkaline solution to carry out a second hydrolysis.

[0043] More preferably, the alkaline solution in condition (f) is selected from sodium hydroxide solution, sodium carbonate solution, potassium carbonate solution or cesium carbonate solution;

[0044] And / or, the molar ratio of the compound of formula (VI) to the alkaline solution is 1:2 to 4.

[0045] More preferably, X in compounds of formula (V) and (VI) is bromine.

[0046] The present invention also provides an intermediate compound for the preparation of leferistant or benzofuran-6-carboxylic acid, comprising compounds as shown in formula (I):

[0047]

[0048] Where X is a halogen.

[0049] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0050] 1. The synthesis of benzofuran-6-carboxylic acid by the method described in this invention has not been reported before, and has a certain degree of novelty;

[0051] 2. The method for preparing benzofuran-6-carboxylic acid described in this invention replaces sodium acetate and acetic acid with acetic anhydride, resulting in higher atom economy. The cyclization reaction conditions are optimized to make it more suitable for industrial production. The purity of the obtained benzofuran-6-carboxylic acid can reach more than 90%. The reaction route is short and the raw materials are cheap and readily available, making the reaction more economical.

[0052] 3. The method for preparing benzofuran-6-carboxylic acid described in this invention avoids the use of controlled reagents (acetic anhydride is a Class II precursor chemical that can be purchased for industrial production), heavy metals, and carbon monoxide. The reaction process is mild, avoiding high-pressure operation and high-temperature heating time of about 8 hours, which effectively reduces the reaction cost.

[0053] 4. The preparation method of benzofuran-6-carboxylic acid described in this invention optimizes the cyclization conditions, making it more suitable for industrial production and significantly improving the yield. The overall yield of the preparation method described in this invention is over 75% (based on compound (V), while the yield of existing technologies such as patent CN104797574 is only 48.11%. Attached Figure Description

[0054] Figure 1 This is a schematic diagram of the synthetic route of the preparation method described in this invention;

[0055] Figure 2 The mass spectrum of compound (Ⅰ) in Example 1;

[0056] Figure 3 The mass spectrum of compound (II) in Example 5;

[0057] Figure 4 The mass spectrum of compound (V) in Example 9;

[0058] Figure 5 The hydrogen spectrum of compound (Ⅰ) in Example 1;

[0059] Figure 6 The hydrogen spectrum of compound (II) in Example 5;

[0060] Figure 7 The hydrogen spectrum of compound (V) in Example 9 is shown. Detailed Implementation

[0061] This invention provides a method for preparing the lefitter intermediate benzofuran-6-carboxylic acid, comprising the following steps:

[0062] S1, Compound (I) reacts with acetic anhydride under heating conditions to undergo a ring-closing reaction to obtain Compound (II);

[0063]

[0064] Where X is a halogen;

[0065] This invention selects compound (I) for a ring-closure reaction with acetic anhydride and optimizes the reaction conditions, eliminating costly reaction conditions such as high pressure, effectively improving the atom economy of the ring-closure reaction and reducing the reaction cost. In some specific embodiments of this invention, the heating temperature for the ring-closure reaction is preferably 100-150°C, more preferably 115-140°C, and even more preferably 130°C; the reaction time for the ring-closure reaction is preferably 5-12 hours, more preferably 6-8 hours. In some specific embodiments of this invention, the mass ratio of compound (I) to the volume ratio of acetic anhydride is preferably 1:1-20, more preferably 1:5. In this invention, the substituent X in compounds (I) and (II) is selected from F, Cl, or Br; in some specific embodiments of this invention, the substituent X in compound (I) is Br.

[0066] In some specific embodiments of the present invention, the compound of formula (I) can be prepared by a method comprising the following steps:

[0067]

[0068] Where X is a halogen;

[0069] A1, Compound (V) reacts with a haloacetic acid ester under heating conditions to give compound (VI);

[0070] A2, compound (VI) undergoes a second hydrolysis under alkaline conditions to yield compound (I).

[0071] In some specific embodiments of the present invention, the heating temperature in step A1 is preferably 40–100°C, more preferably 60–75°C, and even more preferably 70°C; the reaction time in step A1 is preferably 1–6 h, more preferably 2–3 h. In some specific embodiments of the present invention, the haloacetic ester mentioned in step A1 includes, but is not limited to, one or more of methyl chloroacetate, ethyl chloroacetate, benzyl chloroacetate, and isopropyl chloroacetate, preferably methyl chloroacetate or ethyl chloroacetate, and even more preferably methyl chloroacetate. In some specific embodiments of the present invention, the molar ratio of compound (V) to haloacetic ester in step A1 is preferably 1:1–2, more preferably 1:1.2.

[0072] In this invention, the alkaline conditions described in step A2 are preferably pH ≥ 12. In some specific embodiments of this invention, after obtaining compound (VI) according to step A1, it is separated and mixed with an alkaline solution for a second hydrolysis to obtain compound (I); the alkaline solution includes, but is not limited to, sodium hydroxide solution, sodium carbonate solution, potassium carbonate solution, or cesium carbonate solution; preferably, the molar ratio of compound (VI) to alkaline solution is 1:2 to 4. In some specific embodiments of this invention, the substituent X in compounds (V) and (VI) can be F, Cl, or Br, preferably Br.

[0073] S2, Compound (II) and Compound (III) undergo a catalytic reaction under the catalysis of n-butyllithium to obtain Compound (IV), which then undergoes a first hydrolysis reaction under alkaline conditions to obtain benzofuran-6-carboxylic acid;

[0074]

[0075] Where X is a halogen.

[0076] This invention selects n-butyllithium as the catalyst. In some specific embodiments of this invention, the catalytic reaction is carried out under the protection of a protective gas, which can be nitrogen. In step S2 of this invention, a protective gas replaces the higher pressure reaction conditions. The temperature of the catalytic reaction is preferably -78 to -20°C, more preferably -70 to -65°C. The reaction time of the catalytic reaction is preferably 0.5 to 2 hours, more preferably 1 to 1.5 hours. In some specific embodiments of this invention, the molar ratio of compound (II) to compound (III) is preferably 1:1.5 to 2.5, more preferably 1:2.

[0077] In this invention, the preferred alkaline condition is a pH value ≥ 12. In this invention, after obtaining compound (IV) through the catalytic reaction, no separation is required; an alkaline substance is directly added to the reaction solution to adjust the pH to alkaline, thus initiating the first hydrolysis reaction to obtain benzofuran-6-carboxylic acid. The alkaline substance includes, but is not limited to, sodium hydroxide, potassium hydroxide, or lithium hydroxide. In some specific embodiments of this invention, the substituent X in compound (I) can be F, Cl, or Br, preferably Cl.

[0078] In this invention, the reaction time of each step in the preparation of benzofuran-6-carboxylic acid can be specifically determined using conventional laboratory monitoring methods (such as TLC monitoring). The decision to continue the reaction is made based on the monitoring results, and further purification is selected as needed after the reaction is completed. Commonly used purification methods in the art are applicable to this invention.

[0079] The technical solutions provided by the present invention will be described in detail below with reference to the embodiments, but they should not be construed as limiting the scope of protection of the present invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions or as recommended by the manufacturer.

[0080] Example 1 Synthesis of 2-(4-bromo-2-methaneyl-phenoxy)(I)

[0081] At room temperature, 4-bromo-2-hydroxybenzaldehyde (2, 10 g, 49.75 mmol), potassium carbonate (13.75 g, 99.50 mmol), potassium iodide (8.26 g, 49.75 mmol), and acetonitrile (100 ml) were added to a three-necked flask and stirred until 4-bromo-2-hydroxybenzaldehyde was completely dissolved. Then, methyl chloroacetate (6.48 g, 59.70 mmol) was added, and the mixture was heated to 70 °C and reacted for 2 h. After the reaction was cooled to room temperature, the pH was adjusted to about 3, and the mixture was extracted with ethyl acetate (100 ml × 2). The organic phases were combined, washed with saturated brine (100 ml × 2), and evaporated to dryness to obtain 14.16 g of ethyl 2-(5-bromo-2-formylphenoxy)acetate as a yellow solid.

[0082] The obtained yellow solid ethyl 2-(5-bromo-2-formylphenoxy) was dissolved in 50 ml of methanol, and 100 ml of 2 M sodium hydroxide solution was added. The mixture was stirred at room temperature for 1 h, and the pH was adjusted to 2-3. The mixture was extracted with ethyl acetate (200 ml × 2), and the organic phases were combined and evaporated to dryness under reduced pressure to obtain 12.63 g of yellow solid 2-(4-bromo-2-methaneylphenoxy), with a yield of 98.0%.

[0083] mp 147.3~151.4℃, HPLC purity 90.15%. ESI-MS m / z 256.89 [M+H]+. 1H NMR (400MHz, CDCl3): δ 10.36 (s, 1H), 7.74 (d, J=8.3Hz, 1H), 7.34 (dd, J=8.2, 1.2Hz, 1H), 7.12 (d, J=1.6Hz, 1H), 4.83 (s, 2H).

[0084] Example 2 Synthesis of 2-(4-bromo-2-methaneyl-phenoxy)acetic acid (I)

[0085] At room temperature, 4-bromo-2-hydroxybenzaldehyde (2.5 g, 24.87 mmol), potassium carbonate (6.88 g, 49.75 mmol), potassium iodide (4.95 g, 29.85 mmol), and acetonitrile (50 ml) were added to a three-necked flask and stirred until 4-bromo-2-hydroxybenzaldehyde was completely dissolved. Then, ethyl chloroacetate (5.40 g, 49.75 mmol) was added, and the mixture was heated to reflux. After reacting for 1 h, the mixture was cooled to room temperature, and the pH was adjusted to about 3. The mixture was extracted with ethyl acetate (50 ml × 2). The organic phases were combined and washed with saturated brine (50 ml × 2). The mixture was then evaporated to dryness to obtain 5.32 g of ethyl 2-(5-bromo-2-formylphenoxy)acetate as a yellow solid.

[0086] The obtained yellow solid 2-(5-bromo-2-formylphenoxy)acetic acid was dissolved in 30 ml of methanol, and 2 M sodium hydroxide solution (50 ml) was added. The mixture was stirred at room temperature for 1 h, the pH was adjusted, and the mixture was extracted with ethyl acetate (200 ml × 2). The organic phases were combined and evaporated to dryness to obtain yellow solid 2-(4-bromo-2-methaneyl-phenoxy)acetic acid (4.43 g), with a yield of 98.85%.

[0087] mp 147.3~151.4℃, HPLC purity 91.24%, ESI-MS m / z 256.89[M+H]+.

[0088] Example 3 Synthesis of 2-(4-bromo-2-methaneyl-phenoxy)acetic acid (I)

[0089] At room temperature, 4-bromo-2-hydroxybenzaldehyde (2.20 g, 99.49 mmol), potassium carbonate (20.63 g, 149.24 mmol), potassium iodide (33.03 g, 198.99 mmol), and acetonitrile (200 ml) were added to a three-necked flask and stirred until 4-bromo-2-hydroxybenzaldehyde was completely dissolved. Then, benzyl chloroacetate (16.97 g, 99.49 mmol) was added, and the mixture was heated to 40 °C and reacted for 6 h. After the reaction was cooled to room temperature, the pH was adjusted to 2, and the mixture was extracted with ethyl acetate (100 ml × 2). The organic phases were combined, washed with saturated brine (100 ml × 2), and evaporated to dryness to obtain 20.34 g of ethyl 2-(5-bromo-2-formylphenoxy)acetate as a yellow solid.

[0090] The obtained yellow solid ethyl 2-(5-bromo-2-formylphenoxy)acetic acid was dissolved in 100 ml of methanol, and 2 M sodium hydroxide solution (200 ml) was added. The mixture was stirred at room temperature for 1 h, and the pH was adjusted to 2. The mixture was extracted with ethyl acetate (200 ml × 2), and the organic phases were combined and evaporated to dryness to obtain 16.85 g of yellow solid 2-(4-bromo-2-methaneyl-phenoxy)acetic acid, with a yield of 94.02%.

[0091] mp 147.3~151.4℃, HPLC purity 95.56%, ESI-MS m / z 256.89[M+H]+.

[0092] Example 4 Synthesis of 2-(4-bromo-2-methaneyl-phenoxy)acetic acid (I)

[0093] At room temperature, 4-bromo-2-hydroxybenzaldehyde (2.20 g, 99.49 mmol), potassium carbonate (20.63 g, 149.24 mmol), potassium iodide (33.03 g, 198.99 mmol), and acetonitrile (100 ml) were added to a three-necked flask and stirred until 4-bromo-2-hydroxybenzaldehyde was completely dissolved. Then, benzyl chloroacetate (22.04 g, 119.39 mmol) was added, and the mixture was heated to 40 °C and reacted for 6 h. After the reaction was cooled to room temperature, the pH was adjusted to 3, and the mixture was extracted with ethyl acetate (100 ml × 2). The organic phases were combined, washed with saturated brine (100 ml × 2), and evaporated to dryness to obtain 28.56 g of yellow solid.

[0094] The obtained solid was dissolved in 200 ml of methanol, and 100 ml of 2 M sodium hydroxide solution was added. The mixture was stirred at room temperature for 1 h, and the pH was adjusted to 3. The mixture was extracted with ethyl acetate (100 ml × 2). The organic phases were combined, evaporated to dryness, and slurried with petroleum ether to give a yellow solid 3 (25.27 g), with a yield of 98.03%. The HPLC purity was 95.56%, and the ESI-MS m / z was 256.89 [M+H]+.

[0095] Example 5 Synthesis of 6-bromobenzofuran(II)

[0096] At room temperature, 2-(4-bromo-2-methaneyl-phenoxy)acetic acid (3, 10.39 g, 40.11 mmol) and acetic anhydride (50 ml) were added to a three-necked flask. The mixture was stirred and heated to 130 °C. After reacting for 8 h, the temperature was lowered to room temperature, water was added, and the pH was adjusted to approximately 9. The organic phases were combined with ethyl acetate (50 ml × 2) and evaporated to dryness to obtain a dark brown oily substance. Column chromatography was used to separate the oil into a colorless liquid 6-bromobenzofuran (4, 7.62 g), with a yield of 96.43%. The HPLC purity was 96.34%.

[0097] ESI-MS m / z 214.94[M+18]+. 1H NMR (400MHz, CDCl3) δ7.71 (s, 1H), 7.62 (d, J=2.2Hz, 1H), 7.48 (d, J=8.3Hz, 1H), 7.38 (dd, J=8.3, 1.6Hz, 1H), 6.77 (dd, J=2.2, 0.9Hz, 1H).

[0098] Example 6 Synthesis of 6-bromobenzofuran(II)

[0099] At room temperature, 2-(4-bromo-2-methaneyl-phenoxy)acetic acid (3, 40 g, 154.41 mmol) and acetic anhydride (400 ml) were added to a three-necked flask. The mixture was stirred and heated to 150 °C. After reacting for 5 h, the temperature was lowered to room temperature, water was added, and the pH was adjusted to about 9. The organic phases were combined with ethyl acetate (400 ml × 2), and the organic phases were evaporated to dryness to obtain a dark brown oily substance. The product was separated by column chromatography to obtain a colorless liquid (4, 29.09 g), with a yield of 95.62%.

[0100] The HPLC purity was 97.12%, and the ESI-MS m / z was 214.94 [M+18]+.

[0101] Example 7 Synthesis of 6-bromobenzofuran(II)

[0102] At room temperature, 2-(4-bromo-2-methaneyl-phenoxy)acetic acid (3.5 g, 19.30 mmol) and acetic anhydride (5 ml) were added to a three-necked flask. The mixture was stirred and heated to 100 °C. After reacting for 12 h, the temperature was lowered to room temperature, water was added, and the pH was adjusted to approximately 9. The organic phases were combined with ethyl acetate (30 ml × 2) and evaporated to dryness to obtain a dark brown oily substance. The product was separated by column chromatography to obtain a colorless liquid 6-bromobenzofuran (4, 3.66 g), with a yield of 96.15% and an HPLC purity of 96.81%.

[0103] ESI-MS m / z 214.94[M+18]+.

[0104] Example 8 Synthesis of 6-bromobenzofuran(II)

[0105] At room temperature, 2-(4-bromo-2-methaneyl-phenoxy)acetic acid (3, 30 g, 115.81 mmol) and acetic anhydride (600 ml) were added to a three-necked flask. The mixture was stirred and heated to 140 °C. After reacting for 6 h, the temperature was lowered to room temperature, water was added, and the pH was adjusted to approximately 9. The organic phases were combined with ethyl acetate (400 ml × 2) and evaporated to dryness to obtain a dark brown oily substance. Column chromatography was used to separate the oil into a colorless liquid 6-bromobenzofuran (4, 21.68 g), with a yield of 95.02%. The HPLC purity was 97.34%, and the ESI-MS m / z was 214.94 [M+18]+.

[0106] Example 9 Synthesis of benzofuran-6-carboxylic acid

[0107] Under N2 atmosphere, 6-bromobenzofuran (4, 1.77 g, 8.98 mmol) and anhydrous tetrahydrofuran (20 ml) were added to a three-necked flask. After cooling to -68 °C, a 2.5 M n-butyllithium THF solution (7.2 ml, 17.97 mmol) was added dropwise, and the temperature was controlled below -65 °C. After the addition was complete, the reaction was allowed to proceed at low temperature for 1 h. Then, benzyl chloroformate (3.06 g, 17.97 mmol) was added dropwise to the reaction system, and the temperature was controlled below -50 °C. After the reaction was allowed to proceed at low temperature for 2 h, the temperature was raised to room temperature, and a 2 M sodium hydroxide solution (40 ml) was added. The mixture was stirred overnight at 70 °C. After the reaction was complete, the pH was adjusted to approximately 2, and the mixture was extracted with ethyl acetate (20 ml × 2). The organic phases were combined and evaporated to dryness to obtain a black liquid. The liquid was separated by column chromatography to obtain benzofuran-6-carboxylic acid (1, 1.20 g), with a yield of 82.35%.

[0108] mp 186.8~188.2℃, HPLC purity 94.30%, ESI-MS m / z 161.03 [MH]+. 1H NMR (600MHz, CDCl3) δ 8.30 (s, 1H), 8.04 (dd, J=8.1, 1.3Hz, 1H), 7.80 (d, J=2.1Hz, 1H), 7.68 (d, J=8.1Hz, 1H), 6.86 (dd, J=2.1, 0.9Hz, 1H).

[0109] Example 10 Synthesis of benzofuran-6-carboxylic acid

[0110] Under N2 atmosphere, 6-bromobenzofuran (4.3 g, 15.23 mmol) and anhydrous tetrahydrofuran (25 ml) were added to a three-necked flask. After cooling to -68°C, a 2.5 M n-butyllithium THF solution (12.2 ml, 30.50 mmol) was added dropwise, and the temperature was controlled below -65°C. After the addition was complete, the reaction was allowed to proceed at low temperature for 1 h. Benzyl chloroformate (5.21 g, 30.50 mmol) was then added dropwise to the reaction system, and the temperature was controlled below -50°C. After reacting at low temperature for 2 h, the temperature was raised to room temperature, and a 4 M potassium hydroxide solution (20 ml) was added. The mixture was stirred overnight at 70°C. After the reaction was complete, the pH was adjusted to approximately 3, and the mixture was extracted with ethyl acetate (30 ml × 2). The organic phases were combined, evaporated to dryness to obtain a black liquid, and separated by column chromatography to obtain benzofuran-6-carboxylic acid (1, 2.10 g) with a yield of 85.06% and an HPLC purity of 95.21%.

[0111] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing the lefitter intermediate benzofuran-6-carboxylic acid, characterized in that, Includes the following steps: S1, Compound (I) reacts with acetic anhydride under heating conditions to undergo a ring-closing reaction to obtain Compound (II); Where X is a halogen; S2, Compound (II) and Compound (III) undergo a catalytic reaction under the catalysis of n-butyllithium to obtain Compound (IV), which then undergoes a first hydrolysis reaction under alkaline conditions to obtain benzofuran-6-carboxylic acid; Where X is a halogen; In step S2, the catalytic reaction is carried out under the protection of a protective gas, and the temperature of the catalytic reaction is -78 to -20°C. In step S2, the alkaline condition is pH ≥ 12.

2. The preparation method according to claim 1, characterized in that, In step S1, the heating temperature is 100–150°C, and the ring-closing reaction time is 5–12 h.

3. The preparation method according to claim 1 or 2, characterized in that, In step S1, the mass ratio of compound (Ⅰ) to the volume ratio of acetic anhydride is 1:1 to 20.

4. The preparation method according to claim 1, characterized in that, The molar ratio of compound (II) to compound (III) is 1:1.5 to 2.

5.

5. The preparation method according to claim 1, characterized in that, After the catalytic reaction is completed, an alkaline substance is added to the reaction solution to adjust the pH value, and the first hydrolysis reaction is carried out to obtain benzofuran-6-carboxylic acid.

6. The preparation method according to claim 1, characterized in that, In both compounds (I) and (II), X is bromine.

7. The preparation method according to claim 1, characterized in that, The preparation method of compound (I) includes the following steps: Where X is a halogen; A1, Compound (V) reacts with a haloacetic acid ester under heating conditions to give compound (VI); A2, compound (VI) undergoes a second hydrolysis under alkaline conditions to yield compound (I).

8. The preparation method according to claim 7, characterized in that, The preparation method of compound (I) includes one or more of the following conditions: (a) In step A1, the heating temperature is 40–100°C; (b) In step A1, the haloacetic ester is selected from methyl chloroacetate; (c) In step A1, the molar ratio of compound (V) to haloacetic acid ester is 1:1 to 2; (d) In step A1, the reaction time is 1 to 6 hours; (e) In step A2, the alkaline condition is pH ≥ 12; (f) In step A2, the compound of formula (VI) is mixed with an alkaline solution to carry out a second hydrolysis.

9. The preparation method according to claim 8, characterized in that, The alkaline solution described in condition (f) is selected from sodium hydroxide solution, sodium carbonate solution, potassium carbonate solution or cesium carbonate solution; And / or, the molar ratio of the compound of formula (VI) to the alkaline solution is 1:2 to 4.

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