Preparation method of LH-1801 key intermediate

Abstract

The invention relates to the technical field of organic synthesis, and particularly provides a preparation method of an LH-1801 key intermediate, the target product key intermediate is (2-bromo-5-chloro-4-((5-ethylthiophene-2-yl) methyl) phenyl) methanol, a compound 2 and oxalyl chloride are subjected to an acylating chlorination reaction, and a compound 3 is obtained. Then carrying out Friedel-Crafts acylation reaction with 2-ethylthiophene under the action of aluminum trichloride, and carrying out one-step reduction reaction to obtain a target product 1; the preparation method provided by the invention greatly shortens the reaction time, has the advantages of low raw material cost, high product purity, high yield and the like, is very environment-friendly, and is suitable for industrial amplification.

Description

Technical Field

[0001] The 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 good hypoglycemic effect in vivo. It is indicated for type 1 and type 2 diabetes. It is a Class I anti-diabetic new drug candidate with independent intellectual property rights jointly developed by the Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Jiangsu Lianhuan Pharmaceutical Co., Ltd.

[0005] Systematic preclinical studies have shown that LH-1801 has excellent SGLT2 inhibitory activity, can improve hyperglycemia in spontaneous type 2 diabetes model mice and STZ-induced type 1 diabetes model mice, and has the characteristics of low onset dose and significant hypoglycemic effect. LH-1801 has better efficacy than the marketed drug dapagliflozin in multiple animal models, and has good pharmacokinetic properties and safety in rats and dogs. It is a safe, effective, quality-controlled anti-diabetic clinical candidate drug with good drug development prospects.

[0006] At present, the existing technology mainly includes the following two routes:

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

[0008]

[0009] The obvious disadvantage of the above synthetic route is that the diazotization reaction is carried out in a sulfuric acid medium, the ester is severely hydrolyzed, resulting in a very low yield, and 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. CN113429379 (A) of Jiangsu Faande Pharmaceutical Technology Co., Ltd. uses compound 2-chloro-4-methylbenzoic acid A1 as raw material, obtains benzyl bromide A4 through bromination, esterification, and bromination of the methyl side chain of the benzyl ring, and then converts benzyl bromide A4 into methyl ether, acyl Friedel-Crafts reaction, and reduces to obtain A8, and finally removes methyl ether and hydrolyzes to obtain the target compound A10. The reaction equation is as follows:

[0011]

[0012] The starting material A1 of this route is expensive and difficult to source. The obvious process disadvantages are that the bromination reaction conditions in steps A3-A4 are harsh and require a large amount of initiator AIBN; boron tribromide is used for demethylation in steps A8-A9, which has a great impact on the environment; the route has long steps and low yield, resulting in high raw material costs, which is obviously not suitable for large-scale 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 a 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 to undergo Friedel-Crafts acylation to obtain compound 4;

[0018] S3 and compound 4 are subjected to reduction reaction 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 the acid chloride is preferably 1:1.3.

[0025] In some embodiments, in step S1, compound 2 is mixed with dichloromethane to obtain a reaction system, and after dropwise addition, sampling is performed to determine whether the reaction endpoint has been reached. The specific determination method includes detecting the reaction liquid, HPLC tracking and detecting the reaction liquid, and determining whether the reaction is completed. When the molar amount of compound 2 / (compound 2+compound 3) accounts for no more than 1%, the reaction is judged to be complete, and then the solvent is removed under reduced pressure, and dichloromethane is added to redissolve to obtain a dichloromethane solution containing compound 3, which is directly used for the reaction in S2.

[0026] In some embodiments, in step S2: the catalyst is added to dichloromethane under a nitrogen atmosphere and mixed, then the dichloromethane solution containing compound 3 obtained in S1 is slowly added, and 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, and the catalyst is anhydrous aluminum chloride.

[0027] In some embodiments, in step S2, the molar ratio of the catalyst to 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, and after the addition is completed, the mixture is kept at 20-30° C. for 2 h, and the reaction liquid 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, and 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, in step S2, after the insulation reaction is completed, the step further includes adding the obtained reaction solution to 10% dilute hydrochloric acid, stirring for 15 minutes, standing to separate the liquids, extracting the aqueous phase once with dichloromethane, combining the organic phases, washing the organic phase once with water to obtain a dichloromethane organic phase, removing the solvent from the dichloromethane organic phase under reduced pressure, adding a crystallization solvent to the residue for recrystallization, and filtering 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 mixed and dissolved with tetrahydrofuran, the temperature is maintained at 15-25° C., a first reducing agent is first added dropwise, and after the addition is complete, a second reducing agent is added dropwise to obtain compound 1 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 cooperate with the carbonyl oxygen atom to form a stable complex, which enhances the electropositivity of the carbonyl carbon, making the carbon atom more susceptible to attack by the first reducing agent. The first reducing agent reduces the carbon-oxygen double bond in the carbonyl group to a carbon-hydrogen bond to generate the target product. The second reducing agent increases the electrophilicity of the carbonyl carbon, making the reduction reaction easier to occur, helping to improve the selectivity of the reaction, and making the reduction reaction more directional on the target carbonyl group. This reduces the difficulty of the reaction, improves the efficiency of the reaction and the yield of the target product.

[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 ratio of the reducing agent used, the faster the reaction rate. When the reducing agent is used in too high a proportion, it is not conducive to the subsequent quenching treatment.

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

[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, and then water is added dropwise, and the mixture is neutralized with a sodium bicarbonate solution to a pH of 7-8, and the mixture is allowed to stand for stratification, and the aqueous phase is extracted once with dichloromethane, and the organic phases are combined, and the organic phases are washed with a 5% sodium bicarbonate solution and a 5% sodium chloride solution in sequence, and the aqueous layer is discarded, and the lower organic phase is taken, and the organic phase is concentrated under reduced pressure to remove the solvent to obtain an oily crude product, a crystallization solvent is added, the temperature is raised to dissolve, and the temperature is slowly lowered to 5-10°C, and a white solid compound 1 is obtained after filtration. 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] Compared with the prior art, the present invention has the following beneficial effects:

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

[0045] The invention has the advantages of low raw material cost, high product purity and yield, etc., 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 drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. 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 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 described embodiments 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 creative work are within the scope of protection of the present invention.

[0049] In addition, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of the features. In the description of this application, the meaning of "plurality" is two or more, unless otherwise clearly and specifically defined.

[0050] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the embodiments of the present invention belong. If the definitions set forth in this section are contrary to or otherwise inconsistent with the 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 all conventional methods. Unless otherwise specified, the materials, reagents and instruments used are all conventional materials, reagents and instruments in the art, and can be obtained by those skilled in the art through commercial channels.

[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 range upper limit or preferred value with any range lower limit or preferred value, regardless of whether the range is disclosed separately. For example, when a range of "1 to 5" is disclosed, the described range should be interpreted as including the range "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 end values ​​and all integers and fractions within the range. In the present specification and claims, range definitions can be combined and / or interchanged, and if not otherwise stated, these ranges include all subranges contained therein.

[0053] The preparation method of the key intermediate of LH-1801 of the present invention, its main synthesis path 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, and the yield of lithium aluminum tetrahydride is 72% and the reaction time is 3 hours. However, the process safety is poor and it is difficult to scale up production.

[0060] Prior art, WO Patent 2013045495A1, discloses that a compound 6 is reduced with triethylsilane and trifluoroacetic acid to obtain 7, and 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] In view of the shortcomings of the existing reduction process, the inventors found that the composite reduction system of borane dimethyl sulfide and boron trifluoride tetrahydrofuran can reduce the carbonyl and ester groups at the same time, greatly simplifying the process operation and shortening the reaction cycle. Compared with the two-step reduction method, it has the advantages of safe process operation and good reaction selectivity, thus forming an advanced one-step reduction process.

[0064] In order to illustrate the advancedness of the process of the present application, the following specific examples are now described in detail:

[0065] Example 1

[0066] S1: Preparation of compound 3

[0067] In a 2000ml four-necked reaction bottle, 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 drop oxalyl chloride (138.39g, 1.09mol); after the addition, stir for 10min, remove the ice bath and raise the temperature to 20-30°C. The reaction solution gradually becomes clear, and after continuing to stir for 0.5h, concentrate to dryness, add dichloromethane (800ml) to dissolve, and obtain a dichloromethane solution of compound (3);

[0068] S2: Preparation of compound 4

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

[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 the addition was completed, the mixture was stirred for 15 min, and the liquid was separated. The aqueous phase was extracted once with dichloromethane (500 mL); the organic phases were combined, 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, isopropanol (270 mL) and n-heptane (1000 mL) were added, the temperature was raised to 60° C. to dissolve, the temperature was lowered for crystallization, and the filter cake was dried at 45-50° C. and 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) for exothermic reaction, and control 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, dropwise add boron trifluoride tetrahydrofuran (11.01 g, 0.077 mol), and control 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%", and the reaction is completed.

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

[0074] S303, the organic phase was desolventized (40-50°C, -0.01Mpa) to obtain 10.21g of an oily crude product, heptane (100ml) and isopropanol (5ml) were added, and the oil temperature 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 and dried at 50-60°C under negative pressure to obtain 8.31g 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 (73.36 g, 0.58 mol)

[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 (90.75 g, 0.715 mol)

[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 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 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 difference between this embodiment and embodiment 1 is that borane dimethyl sulfide solution (25 ml, 0.05 mol) is added dropwise 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 difference between this embodiment and embodiment 1 is that borane dimethyl sulfide solution (62.5 ml, 0.125 mol) is added dropwise for exothermic reaction, the internal temperature is controlled not to exceed 40°C, and after the addition is completed, stirring is performed 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 difference between this embodiment and embodiment 1 is that borane dimethyl sulfide solution (25 ml, 0.05 mol) is added dropwise 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; borane dimethyl sulfide solution (69.3 ml, 0.077 mol) is added dropwise at an internal temperature of 20-30°C.

[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 difference between this embodiment and embodiment 1 is that boron trifluoride tetrahydrofuran (7.15 g, 0.05 mol) is added dropwise 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 (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 while having high purity, but also the preparation process is easy to scale up industrially, 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 protection scope 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, It is 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 Friedel-Crafts acylation to obtain compound 4; S3 and compound 4 are subjected to reduction reaction in the presence of a composite reducing agent to obtain compound 1; The reaction formula is as follows:

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

5. The method for preparing the key intermediate of LH-1801 as claimed in claim 4, It is characterized in that 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 as claimed in claim 4, It is characterized in that In step S2, after the insulation reaction is completed, the obtained reaction solution is added into 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 as claimed in claim 6, It is characterized in that 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 as claimed in claim 1, It is characterized in that Step S3 comprises: after the compound 4 is mixed and dissolved with tetrahydrofuran, a first reducing agent is first added dropwise, and after the addition is complete, a second reducing agent is added dropwise to obtain the compound 1 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.

9. The method for preparing the key intermediate of LH-1801 as claimed in claim 8, It is characterized in that When the first reducing agent is added dropwise, the temperature does not exceed 40°C, and the reaction is kept warm for 15 minutes after the addition is completed. When the second reducing agent is added dropwise, the temperature does not exceed 40°C, and after the addition is completed, it is heated to 50-55°C and the reaction is kept warm for 2 hours.

10. The method for preparing the key intermediate of LH-1801 according to claim 9, It is characterized in that 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, and then water is added dropwise, and the mixture is neutralized with sodium bicarbonate solution to pH = 7-8, and the mixture is allowed to stand and separate into layers. 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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