A preparation method of an LH-1801 key intermediate

Abstract

The application relates to the technical field of organic synthesis, and particularly discloses a preparation method of a key intermediate of LH-1801, wherein the target product key intermediate is (2-bromo-5-chloro-4-((5-ethylthiophene-2-yl)methyl)phenyl)methanol, the compound 2 and oxalyl chloride are subjected to an acyl chloride reaction, then the compound 2-bromo-5-chloro-4-((5-ethylthiophene-2-yl)methyl)phenyl)methanol is subjected to a Friedel-Crafts acylation reaction under the action of aluminum chloride, and finally the target product 1 is obtained through a one-step reduction reaction; the preparation method has the advantages of greatly shortened reaction time, low raw material cost, high product purity and yield, high environmental friendliness and suitability for industrial amplification.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a method for preparing a key intermediate of LH-1801. Background Art

[0002] The chemical name of the key intermediate of LH-1801 is (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol, CAS: [2713561-79-4], and its structural formula is as follows:

[0003]

[0004] LH-1801 is a new SGLT2 inhibitor with excellent hypoglycemic effects in vivo. It is indicated for type 1 and type 2 diabetes. It is a Class I anti-diabetic drug candidate with independent intellectual property rights in my country, jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Jiangsu Lianhuan Pharmaceutical Co., Ltd.

[0005] Systematic preclinical studies have demonstrated that LH-1801 exhibits excellent SGLT2 inhibitory activity, ameliorating hyperglycemia in both spontaneous type 2 diabetes and STZ-induced type 1 diabetes mouse models, with a low onset dose and significant glucose-lowering effects. LH-1801 demonstrates superior efficacy to the marketed drug dapagliflozin in multiple animal models and exhibits favorable pharmacokinetic properties and safety in rats and dogs. It is a safe, effective, and quality-controlled antidiabetic clinical candidate with promising drug development prospects.

[0006] Currently, the existing technologies mainly include the following two routes:

[0007] 1. Jiangsu Lianhuan Pharmaceutical Co., Ltd. discloses in Chinese patent CN115819398(A) a method for obtaining target compound 1 using 2-aminoterephthalic acid as a raw material through monoesterification, bromination, Sandmeyer reaction, and acyl Friedel-Crafts reduction. The reaction equation is as follows:

[0008]

[0009] The obvious disadvantages of the above synthetic route are that the diazotization reaction is carried out in a sulfuric acid medium, the ester is severely hydrolyzed, resulting in a very low yield. The final reduction uses lithium aluminum tetrahydride, which has high raw material costs and poor process safety, making it unsuitable for future production.

[0010] 2. Jiangsu Faande Pharmaceutical Technology Co., Ltd. CN113429379(A) uses 2-chloro-4-methylbenzoic acid A1 as a raw material. Through bromination, esterification, and bromination of the phenyl ring methyl side chain, benzyl bromide A4 is obtained. Benzyl bromide A4 is then converted to methyl ether, followed by acyl Friedel-Crafts reaction and reduction to obtain A8. Finally, the methyl ether is removed and hydrolysis is performed to obtain the target compound A10. The reaction equation is as follows:

[0011]

[0012] The starting material A1 in this route is expensive and difficult to source. Significant process drawbacks include the harsh bromination reaction conditions in steps A3-A4, which requires a large amount of the initiator AIBN. The demethylation step A8-A9 uses boron tribromide, which has a significant environmental impact. Furthermore, the route is lengthy and yields are low, resulting in high raw material costs, making it unsuitable for scale-up production.

[0013] In summary, finding a new method for preparing the key intermediate of LH-1801 with the advantages of "low raw material cost, high product purity and yield, and less three wastes" has become a technical problem that needs to be solved urgently. Summary of the Invention

[0014] In view of this, the present invention proposes a method for preparing the key intermediate of LH-1801 with low cost, high purity, high yield and less three wastes.

[0015] The technical solution of the present invention is achieved as follows: The present invention provides a method for preparing a key intermediate of LH-1801, wherein the key intermediate of LH-1801 for preparing the target product is (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol, and the specific preparation steps include:

[0016] S1 and compound 2 react with acyl chloride to generate compound 3;

[0017] S2 and compound 3 react with compound 5 in the presence of a catalyst through a Friedel-Crafts acylation reaction to obtain compound 4;

[0018] S3 and compound 4 are reduced in the presence of a composite reducing agent to obtain compound 1;

[0019] The reaction formula is as follows:

[0020]

[0021] In some embodiments, in step S1, the acyl chloride is one of oxalyl chloride, thionyl chloride, triphosgene and phosphorus trichloride.

[0022] In some embodiments, in step S1, the reaction temperature is 20-30° C., and the acyl chloride is added dropwise.

[0023] In some embodiments, in step S1, the molar ratio of compound 2 to acyl chloride is 1:(1.05-3).

[0024] In some embodiments, the molar ratio of compound 2 to acyl chloride is preferably 1:1.3.

[0025] In some embodiments, in step S1, compound 2 is mixed with dichloromethane to obtain a reaction system. After the dropwise addition, sampling is performed to determine whether the reaction has reached the endpoint. Specific methods for determining whether the reaction has ended include detecting the reaction solution and tracking the reaction solution with HPLC to determine whether the reaction has ended. The reaction is considered complete when the molar ratio of compound 2 / (compound 2 + compound 3) does not exceed 1%. The solvent is then removed under reduced pressure, and dichloromethane is added for redissolution to obtain a dichloromethane solution containing compound 3, which is directly used in the reaction in S2.

[0026] In some embodiments, in step S2: the catalyst is added to dichloromethane under a nitrogen atmosphere and mixed, and then the dichloromethane solution containing compound 3 obtained in S1 is slowly added. After mixing evenly, compound 5 is added dropwise to the mixed solution. After the addition is complete, the mixture is kept warm to react to obtain compound 4. The catalyst is anhydrous aluminum chloride.

[0027] In some embodiments, in step S2, the molar ratio of the catalyst to the compound 2 is (2-5):1.

[0028] In some embodiments, in step S2, the molar ratio of the catalyst to the compound 2 is preferably 3:1.

[0029] In some embodiments, in step S2, the molar ratio of compound 5 to compound 2 is preferably (1-2):1.

[0030] In some embodiments, in step S2, when compound 5 is added dropwise, the reaction temperature is 0-10°C.

[0031] In some embodiments, in step S2, before slowly adding the dichloromethane solution containing compound 3 obtained in S1, the dichloromethane solution containing the catalyst is cooled to 0-5°C, and then the dichloromethane solution containing compound 3 obtained in S1 is added, and stirring is continued for 1 hour to mix evenly.

[0032] In some embodiments, in step S2, compound 5 is added dropwise. After the addition is complete, the mixture is kept at 20-30°C for 2 hours. The reaction solution is tracked and detected by HPLC to determine whether the reaction is complete.

[0033] In some embodiments, in step S2, the method for determining the end of the reaction includes sampling the reaction solution for HPLC detection. When the molar content ratio of compound 3 / (compound 3+compound 4+compound 5) does not exceed 1%, the reaction is ended.

[0034] In some embodiments, after the reaction is completed in step S2, the obtained reaction solution is added into 10% dilute hydrochloric acid, stirred for 15 min, and then allowed to stand and separate. The aqueous phase is extracted with dichloromethane once, and the combined organic phase is washed with water once to obtain a dichloromethane organic phase. The dichloromethane organic phase is subjected to solvent removal under reduced pressure, and the residue is recrystallized from a crystallization solvent to obtain compound 4.

[0035] In some embodiments, the crystallization solvent is at least one of ethanol, isopropanol, n-heptane, hexane, and ethyl acetate.

[0036] In some embodiments, step S3 comprises: after compound 4 is dissolved in tetrahydrofuran, the temperature is maintained at 15-25°C, a first reducing agent is first added dropwise, and then a second reducing agent is added dropwise after the addition of the first reducing agent is completed, and compound 1 is obtained through a reduction reaction; the first reducing agent is one of sodium borohydride, potassium borohydride, borane dimethyl sulfide, triethylsilane, and borane tetrahydrofuran, and the second reducing agent is boron trifluoride tetrahydrofuran.

[0037] In the above embodiments, boron trifluoride in the second reducing agent acts as a Lewis acid and can coordinate with the carbonyl oxygen atom to form a stable complex, thereby enhancing the electropositivity of the carbonyl carbon, making the carbon atom more susceptible to attack by the first reducing agent. The carbon-oxygen double bond in the carbonyl group is reduced to a carbon-hydrogen bond by the first reducing agent to generate the target product. The role of the second reducing agent is to increase the electrophilicity of the carbonyl carbon, thereby facilitating the reduction reaction and improving the selectivity of the reaction, so that the reduction reaction occurs more directionally on the target carbonyl group. Thus, the difficulty of the reaction is reduced, and the efficiency of the reaction and the yield of the target product are improved.

[0038] The molar ratio of compound 4: the first reducing agent: the second reducing agent is 1:(2-5):(2-5).

[0039] The higher the proportion of the above reducing agent, the faster the reaction speed. When the amount of the reducing agent is too high, it is not conducive to subsequent quenching treatment.

[0040] In some embodiments, when the first reducing agent is added dropwise, the temperature does not exceed 40°C, and after the addition is completed, the reaction is maintained for 15 min. When the second reducing agent is added dropwise, the temperature does not exceed 40°C, and after the addition is completed, the temperature is heated to 50-55°C, and the reaction is maintained for 2 h. The reaction solution is detected by HPLC to determine whether the reaction is complete. When the molar content of compound 4 / (compound 1+compound 4) is not more than 1%, the reaction is complete.

[0041] In some embodiments, after the reaction is completed, the temperature is lowered to 10-20°C, methanol is slowly added dropwise to quench, and then the mixture is concentrated under reduced pressure at 40-50°C until it becomes viscous. Dichloromethane is added, followed by water dropwise, and the mixture is neutralized with sodium bicarbonate solution to a pH of 7-8. The mixture is allowed to stand and separate into layers. The aqueous phase is extracted once with dichloromethane, and the organic phases are combined. The organic phases are washed sequentially with 5% sodium bicarbonate solution and 5% sodium chloride solution, the aqueous layer is discarded, and the lower organic phase is removed. The organic phase is concentrated under reduced pressure to remove the solvent to obtain an oily crude product, a crystallization solvent is added, the mixture is heated and dissolved, and the temperature is slowly lowered to 5-10°C. After filtration, a white solid compound 1 is obtained. The crystallization solvent is at least one of ethanol, isopropanol, n-heptane, hexane, and ethyl acetate.

[0042] In some embodiments, the mass ratio of methanol:Compound 4 is (3-10):1.

[0043] The present invention has the following beneficial effects compared to the prior art:

[0044] The present invention provides a method for preparing a key intermediate of LH-1801. Compound 3 is prepared from compound 2 and an acyl chloride, and compound 3 is subjected to a Friedel-Crafts acylation reaction with 2-ethylthiophene. After the reaction is completed, the carbonyl group and the ester group are simultaneously reduced by a composite reducing agent, and the target compound 1 is obtained by crystallization. This synthetic route not only has simple process operation, but also safer reagent use, improved process operation safety, and good reaction selectivity, and can obtain the target product with high yield and high purity.

[0045] The invention has the advantages of low raw material cost, high product purity and yield, is very environmentally friendly, and is suitable for industrial scale-up. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0047] Figure 1 This is an HPLC spectrum for purity detection of (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0048] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0049] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of the technical features being referred to. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. Throughout the description of this application, "plurality" means two or more, unless otherwise specifically defined.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which embodiments of the present invention belong. If the definitions set forth in this section are contrary to or otherwise inconsistent with definitions set forth in the patents, patent applications, published patent applications, and other publications incorporated herein by reference, the definitions listed in this section take precedence over the definitions incorporated herein by reference.

[0051] Unless otherwise specified, the methods used in the following examples are conventional methods. The materials, reagents, and instruments used are conventional materials, reagents, and instruments in the art, unless otherwise specified, and can be obtained commercially by those skilled in the art.

[0052] When an amount, concentration or other value or parameter is expressed as a range, a preferred range or a range defined by a series of upper preferred values ​​and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pairing of any upper range limit or preferred value with any lower range limit or preferred value, regardless of whether the range is disclosed alone. For example, when a range "1 to 5" is disclosed, the described range should be interpreted as including the ranges "1 to 4", "1 to 3", "1 to 2", "1 to 2 and 4 to 5", "1 to 3 and 5", etc. When a numerical range is described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within the range. In the present specification and claims, range definitions may be combined and / or interchanged, and if not otherwise stated, such ranges include all subranges contained therein.

[0053] The preparation method of the key intermediate LH-1801 of the present invention, its main synthetic route is as follows:

[0054]

[0055] Among them, compound 2, chemical name: 5-bromo-2-chloro-4-(methoxycarbonyl)benzoic acid, CAS number: 1061314-04-2.

[0056] Compound 3, chemical name: methyl 2-bromo-5-chloro-4-(chlorocarbonyl)benzoate.

[0057] Compound 4, chemical name: methyl 2-bromo-5-chloro-4-[(5-ethylthiophen-2-yl)carbonyl]benzoate.

[0058] Compound 5, chemical name: 2-ethylthiophene, CAS number: 872-55-9.

[0059] The currently disclosed scheme includes a one-step reduction method using borane dimethyl sulfide and lithium aluminum tetrahydride as reducing agents. The yield of lithium aluminum tetrahydride is 72% and the reaction time is 3 hours. However, the process has poor safety and is difficult to scale up for production.

[0060] Prior art, WO Patent 2013045495A1, discloses a method of reducing compound 6 using triethylsilane and trifluoroacetic acid to obtain compound 7, which is then reacted with sodium borohydride to obtain compound 8. The reaction process is as follows:

[0061]

[0062] This method is completed in two steps and the operation is more complicated.

[0063] To address the shortcomings of existing reduction processes, the inventors discovered that a composite reduction system using borane dimethyl sulfide and boron trifluoride tetrahydrofuran can simultaneously reduce both carbonyl and ester groups, significantly simplifying the process and shortening the reaction cycle. Compared to two-step reduction methods, this method offers advantages in operational safety and high reaction selectivity, resulting in an advanced one-step reduction process.

[0064] In order to illustrate the advanced nature of the process of this application, the following specific examples are provided for detailed description:

[0065] Example 1

[0066] S1: Preparation of compound 3

[0067] In a 2000ml four-necked reaction flask, add 5-bromo-2-chloro-4-(methoxycarbonyl)benzoic acid (160g, 0.55mol) and dichloromethane (800mL), add DMF (0.80g), start stirring, cool in an ice bath, control the temperature at 0-5°C, and slowly add oxalyl chloride (138.39g, 1.09mol) dropwise; after the addition is complete, stir for 10min, remove the ice bath, and raise the temperature to 20-30°C. The reaction solution gradually becomes clear, continue stirring for 0.5h, then concentrate to dryness, add dichloromethane (800ml) and dissolve to obtain a dichloromethane solution of compound (3);

[0068] S2: Preparation of compound 4

[0069] In a 3000ml four-necked reaction flask, add dichloromethane (1000.0mL) and anhydrous aluminum chloride (218.01g, 1.63mol) and cool to 0-5°C in an ice bath. Slowly add a dichloromethane solution of compound 3 (0.55mol) and stir for 1h after addition. Then, add 2-ethylthiophene (91.72g, 0.82mol) dropwise, controlling the internal temperature at 0-5°C for 5 hours. The reaction solution gradually turns brown and is naturally warmed to room temperature. After incubation for 2h, HPLC tracking detection is performed to control the molar content of "compound 3 / (compound 3+compound 4+compound 5) to be less than 1.0%", indicating that the reaction is complete.

[0070] The reaction solution was added dropwise to 10% hydrochloric acid (1400 g) in batches, the temperature was controlled at 0-10° C., and after stirring for 15 minutes after the addition, the liquid was separated, and the aqueous phase was extracted once with dichloromethane (500 mL); the organic phases were combined and washed once with water (500 mL) and 5% sodium chloride solution (500 mL), respectively, to obtain a dichloromethane layer; the organic phase was concentrated to dryness, and isopropanol (270 mL) and n-heptane (1000 mL) were added. The temperature was raised to 60° C. to dissolve the clear solution, and the temperature was lowered for crystallization and filtration. The filter cake was dried at 45-50° C. under a vacuum degree of -0.08 to -0.1 MPa to obtain 155.38 g of a yellow solid with a yield of 73.5% and a purity of 95.28%.

[0071] S3: Preparation of Compound 1

[0072] S301. Add compound 4 (10 g, 0.025 mol) and THF (50 ml) under nitrogen protection, and stir to dissolve; when the internal temperature is 20-25°C, begin to dropwise add borane dimethyl sulfide solution (45 ml, 0.09 mol), and react exothermically, controlling the internal temperature not to exceed 40°C. After the addition is completed, stir for 15 minutes; at an internal temperature of 20-30°C, add boron trifluoride tetrahydrofuran (11.01 g, 0.077 mol), controlling the internal temperature not to exceed 40°C; after the addition is completed, stir at 30-40°C for half an hour, raise the temperature to 50-55°C, and keep the reaction for 2 hours. Take samples for HPLC detection, and control the molar content of "compound 4 / (compound 1 + compound 4) less than 1.0%". The reaction is completed.

[0073] S302, cooling the reaction solution to 10-20°C, adding methanol (30 ml) dropwise, controlling the temperature to be less than 20°C, stirring until no bubbles are generated, and distilling the feed solution under reduced pressure at a water temperature of 40-50°C until it becomes viscous; adding dichloromethane (50 ml), adding water (50 ml) dropwise, neutralizing with 5% sodium bicarbonate solution to pH = 7-8, standing to separate layers, extracting the aqueous phase once with dichloromethane (50 ml), and combining the organic phases; washing the organic phases with 5% sodium bicarbonate solution (50 ml) and 5% sodium chloride solution (50 ml), respectively, and removing the lower organic phase;

[0074] S303, the organic phase was desolvated under reduced pressure (40-50°C, -0.01Mpa) to obtain 10.21 g of an oily crude product, heptane (100 ml) and isopropanol (5 ml) were added, and the oil was stirred at 65°C to dissolve clearly, and the temperature was slowly lowered by 5-10°C. Crystallization was continued for 2 hours, and the solid was filtered to obtain a solid, which was dried at 50-60°C under reduced pressure to obtain 8.31 g of a white solid (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol, with a yield of 93.27% and a purity of 99.42%.

[0075] Example 2

[0076] The difference between this embodiment and embodiment 1 is that the feeding amount of oxalyl chloride is (73.36g, 0.58mol)

[0077] 8.23 g of white solid (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol was obtained with a yield of 92.34% and a purity of 99.47%.

[0078] Example 3

[0079] The difference between this embodiment and embodiment 1 is that the feeding amount of oxalyl chloride is (90.75g, 0.715mol)

[0080] 8.33 g of white solid (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol was obtained with a yield of 93.50% and a purity of 99.57%.

[0081] Example 4

[0082] The difference between this embodiment and embodiment 1 is that the feeding amount of oxalyl chloride is (209.43g, 1.65mol)

[0083] 8.08 g of white solid (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol was obtained with a yield of 90.72% and a purity of 99.36%.

[0084] Example 5

[0085] The only difference between this embodiment and embodiment 1 is that thionyl chloride is used as the acyl chloride, and the feeding amount is (130.85 g, 1.1 mol).

[0086] 8.27 g of white solid (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol was obtained with a yield of 92.83% and a purity of 99.41%.

[0087] Example 6

[0088] The only difference between this embodiment and embodiment 1 is that phosphorus trichloride is used as the acyl chloride, and the feeding amount is (149.69 g, 1.1 mol).

[0089] 8.25 g of white solid (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol was obtained with a yield of 92.57% and a purity of 99.42%.

[0090] Example 7

[0091] The only difference between this example and Example 1 is that borane dimethyl sulfide solution (25 ml, 0.05 mol) is added dropwise to allow for exothermic reaction, the internal temperature is controlled not to exceed 40°C, and after the addition is completed, stirring is carried out for 15 minutes; and boron trifluoride tetrahydrofuran (7.15 g, 0.05 mol) is added dropwise at an internal temperature of 20-30°C.

[0092] 8.17 g of white solid (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol was obtained with a yield of 91.65% and a purity of 99.36%.

[0093] Example 8

[0094] The only difference between this example and Example 1 is that borane dimethyl sulfide solution (62.5 ml, 0.125 mol) is added dropwise to allow for exothermic reaction, while controlling the internal temperature not to exceed 40° C. After the addition is completed, stirring is carried out for 15 minutes; and boron trifluoride tetrahydrofuran (17.88 g, 0.125 mol) is added dropwise at an internal temperature of 20-30° C.

[0095] 8.07 g of white solid (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol was obtained with a yield of 90.60% and a purity of 99.38%.

[0096] Comparative Example 1

[0097] The only difference between this example and Example 1 is that a borane dimethyl sulfide solution (25 ml, 0.05 mol) is added dropwise to allow for an exothermic reaction. The internal temperature is controlled not to exceed 40° C. After the addition is completed, the mixture is stirred for 15 minutes. At an internal temperature of 20 to 30° C., a borane dimethyl sulfide solution (69.3 ml, 0.077 mol) is added dropwise.

[0098] 6.65 g of white solid was obtained with a yield of 74.62% and a purity of 73.66%.

[0099] Comparative Example 2

[0100] The only difference between this example and example 1 is that boron trifluoride tetrahydrofuran (7.15 g, 0.05 mol) is added dropwise to allow for exothermic reaction, while controlling the internal temperature not to exceed 40° C. After the addition is completed, stirring is carried out for 15 minutes; and boron trifluoride tetrahydrofuran (11.01 g, 0.077 mol) is added dropwise at an internal temperature of 20-30° C.

[0101] 2.91 g of white solid was obtained with a yield of 32.66% and a purity of 1.63%.

[0102] It can be seen from the above examples that the preparation method of the present application adopts the technical solution of a composite reducing agent, which can not only effectively improve the yield of the target intermediate and have high purity, but also the preparation process is easy to industrially scale up, does not require the use of hazardous compound raw materials, and has good application prospects.

[0103] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing a key intermediate of LH-1801, wherein the key intermediate of the target product is (2-bromo-5-chloro-4-((5-ethylthiophen-2-yl)methyl)phenyl)methanol, characterized in that: The preparation method comprises the following steps: S1 and compound 2 react with acyl chloride to generate compound 3; S2 and compound 3 react with compound 5 in the presence of a catalyst through a Friedel-Crafts acylation reaction to obtain compound 4; S3 and compound 4 are reduced in the presence of a composite reducing agent to obtain compound 1; Step S3 comprises: after the compound 4 is mixed and dissolved with tetrahydrofuran, first adding a first reducing agent dropwise, and then adding a second reducing agent dropwise after the addition is complete, to obtain compound 1 through a reduction reaction; the first reducing agent is borane dimethyl sulfide or borane tetrahydrofuran, and the second reducing agent is boron trifluoride tetrahydrofuran; when the first reducing agent is added dropwise, the temperature does not exceed 40° C., and after the addition is complete, the temperature is kept at this temperature for 15 minutes; when the second reducing agent is added dropwise, the temperature does not exceed 40° C., and after the addition is complete, the temperature is heated to 50-55° C. and the temperature is kept at this temperature for 2 hours; The reaction formula is as follows: 。 2. The method for preparing the key intermediate of LH-1801 according to claim 1, wherein In step S1, the acyl chloride is one of oxalyl chloride, thionyl chloride, triphosgene and phosphorus trichloride.

3. The method for preparing the key intermediate of LH-1801 according to claim 1, wherein: In step S1, the reaction temperature is 20-30° C., and the acyl chloride is added dropwise.

4. The method for preparing the key intermediate of LH-1801 according to claim 1, wherein In step S2: Compound 3 and a catalyst are mixed in dichloromethane, and then compound 5 is added dropwise. After the addition is complete, the mixture is kept warm for reaction to obtain compound 4, wherein the catalyst is anhydrous aluminum chloride.

5. The method for preparing the key intermediate of LH-1801 according to claim 4, wherein: In step S2, when compound 5 is added dropwise, the reaction temperature is 0-10°C.

6. The method for preparing the key intermediate of LH-1801 according to claim 4, wherein: In step S2, after the insulation reaction is completed, the obtained reaction solution is added to dilute hydrochloric acid, stirred and separated, the aqueous phase is extracted with dichloromethane, the organic phases are combined, the solvent is removed under reduced pressure, the residue is added with a crystallization solvent for recrystallization, and filtered to obtain compound 4.

7. The method for preparing the key intermediate of LH-1801 according to claim 6, wherein: The crystallization solvent is at least one of ethanol, isopropanol, n-heptane, hexane and ethyl acetate.

8. The method for preparing the key intermediate of LH-1801 according to claim 1, wherein: After the reaction is completed, the temperature is lowered to 10-20°C, methanol is slowly added dropwise to quench, and then the mixture is concentrated under reduced pressure at 40-50°C until it becomes viscous. Dichloromethane is added, followed by water dropwise. The mixture is neutralized with sodium bicarbonate solution to a pH of 7-8, and the layers are allowed to stand. The aqueous phase is extracted with dichloromethane, and the organic phases are combined, washed, concentrated, and crystallized to obtain compound 1.

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