Synthesis method of alasset intermediate

Abstract

The invention discloses a synthesis method of an ilastrant intermediate. The synthesis method comprises the following steps: step 1, carrying out condensation reaction on a compound I and ethylamine to obtain a compound II; 2, reducing the compound II to obtain a compound IV; 3, adding a protecting group on the compound IV to obtain a compound V, wherein R of the compound V is one of Boc, Cbz and Fmoc; and 4, carrying out an oxidation reaction on the compound V to obtain a compound III. The invention provides a brand-new low-cost synthetic route suitable for large-scale industrial production of the key intermediate of the Alalistat, relatively mild reaction conditions are adopted in the whole process of the synthetic route, ultralow-temperature or high-risk chemical reagents are not involved, and the production cost and the safety risk are greatly reduced.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical processing technology, specifically to a method for synthesizing an alastan intermediate. Background Technology

[0002] Ellastran is a drug used to treat specific types of breast cancer. It was developed as an oral selective estrogen receptor degrader, primarily for the treatment of patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer who carry an estrogen receptor 1 gene mutation (ESR1).

[0003] The mechanism of action of ellastatin is to bind to estrogen receptors in cancer cells, altering their conformation so that the receptors are recognized and degraded by the cell's own protein degradation mechanisms. This reduces the stimulatory effect of estrogen on these cancer cells, thereby inhibiting tumor growth. This is particularly important for cancers that have developed resistance to traditional endocrine therapy.

[0004] Several methods for synthesizing israsulane groups have been mentioned in the prior art, for example:

[0005] First, a synthetic route for arasyl groups was proposed (Publication No.: CN113348163A). In this route, 7-benzyloxy-3-bromo-1,2-dihydronaphthalene and 2-bromo-5-methoxyacetanilide were used as starting materials to obtain a key intermediate through four steps. The intermediate was chirally resolved, then reacted with N-ethyl-2-(4-formylphenyl)acetamide under acidic conditions to form a Schiff base. The double bond was then reduced and an ethyl group was added under hydrogenation with sodium borohydride acetate, and the acyl group was reduced to obtain the arasyl group. However, this route is costly, and the reduction operation using sodium borohydride and iodine at the end leads to difficulties in controlling API impurities.

[0006] Secondly, (Publication No.: CN117229157A) discloses a new method for synthesizing the alasin group, as follows:

[0007]

[0008] This synthetic method avoids the final reduction with sodium borohydride and iodine. However, when adding ethyl groups to acetaldehyde, it is difficult to avoid the byproducts of adding two ethyl groups in actual experiments. Furthermore, separation and purification are extremely difficult. Acetaldehyde is a toxic impurity, and introducing it in the final step poses a very high risk.

[0009] Secondly, (Publication No. CN118206458A) discloses a method for preparing ellastatin.

[0010]

[0011] Wherein, R2 is a formyl group or R3 is a nitrogen protecting group, and R3 is selected from Boc, Cbz, Fmoc or Bn. This route completes the addition and transformation of functional groups in the intermediates. After the two key intermediates are linked by reductive ammoniation, the final product is obtained by deprotection.

[0012] Finally, (publication number CN119751307A) two combined routes were disclosed:

[0013] Route 1:

[0014]

[0015] Route 2:

[0016]

[0017] R is selected from Boc, Cbz, Fmoc, Bn, Teoc or Tfa. Route 1 uses ethyl bromoethane and then synthesizes formula III through Bouveault aldehyde. However, the synthesis of Bouveault aldehyde requires ultra-low temperature (-80℃) and n-butyllithium reaction. The industrial production equipment requirements and safety levels are very high, which will seriously restrict the production capacity.

[0018] Route 2 involves ethylating bromoethane and then oxidizing the methyl group to obtain formula III. The patent uses tin dioxide to oxidize the methyl group at the end, but the reagent used in the Riley reaction of methyl oxidation is selenium dioxide, not tin dioxide, which is a highly toxic substance. Therefore, this route is not suitable for industrial production.

[0019] Therefore, we propose a method for synthesizing ilass group intermediates. Summary of the Invention

[0020] The purpose of this invention is to provide a method for synthesizing ellagic intermediates to solve the problems that need to be addressed in the background art.

[0021] To achieve the above objectives, the present invention provides the following technical solution: a method for synthesizing an alasin intermediate, the method comprising the following steps:

[0022]

[0023] Step 1: Compound I is condensed with ethylamine to obtain compound II;

[0024] Step 2: Reduce compound II to obtain compound IV;

[0025] Step 3: Remove the protecting group from compound IV to obtain compound V, wherein R in compound V is one of Boc, Cbz, or Fmoc;

[0026] Step 4: Oxidize compound V to obtain compound III.

[0027] The intermediates manufactured in the prior art (publication number: CN11348163A) are reduced using sodium borohydride and iodine. Although the target product can be obtained, this method is prone to problems of difficulty in controlling impurities of active pharmaceutical ingredient (API), which increases the difficulty of subsequent purification. In addition, another route (publication number: CN117229157A) attempts to avoid the use of sodium borohydride and iodine. However, in practice, the addition of ethyl groups to acetaldehyde easily forms byproducts, and acetaldehyde poses a high risk of being introduced as a genotoxic impurity in the final step. Other synthetic routes, such as the Bouveault aldehyde synthesis method, require ultra-low temperature conditions and the reaction of n-butyllithium, which places extremely high demands on industrial production equipment; or the oxidation of methyl groups using tin dioxide, when in fact highly toxic selenium dioxide should be used, which is clearly unsuitable for industrial production. This invention proposes a novel, low-cost synthetic route for key intermediates of the alasmic group suitable for large-scale industrial production. This route includes four steps: first, compound I is condensed with ethylamine to obtain compound II; then, compound II is reduced to compound IV; then, a protecting group is added to compound IV to obtain compound V; finally, the final target product compound III is prepared through an oxidation reaction. The entire process uses relatively mild reaction conditions and does not involve ultra-low temperatures or highly hazardous chemical reagents, greatly reducing production costs and safety risks; and in the first condensation reaction, a variety of common condensing agents and additives are selected, making the reaction more flexible and controllable. The second reduction reaction used conventional and easily handled reducing agents such as sodium borohydride. In the third step, the addition of protecting groups effectively protected the target functional groups from subsequent reactions and facilitated their removal in later steps. In the final oxidation step, sodium hypochlorite was preferred as the oxidant, and potassium bromide and other catalysts were used in conjunction to achieve efficient oxidation at lower temperatures, reducing the possibility of byproduct formation.

[0028] As a further description of the above technical solution:

[0029] In step one, the condensation agent used for the condensation reaction of compound I with ethylamine is one of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU). The added condensation additive is one of 1-hydroxybenzotriazole (HOBT) and 1-hydroxy-7-azabenzotriazole (HOAT). The molar ratio of compound II to the condensation agent is 1:1.0-3.0, and the molar ratio of compound II to the condensation additive is 1:1.0-3.0. The ethylamine is one of ethylamine hydrochloride, ethylamine methanol solution, and ethylamine aqueous solution. The reaction solvent for the condensation reaction is one of dichloromethane, trichloromethane, tetrahydrofuran, methanol, and ethanol. The reaction temperature is 10-35℃, preferably 20-30℃.

[0030] As a further description of the above technical solution:

[0031] The reducing agent selected in step two is one of sodium borohydride, iodine system, borane-THF solution and boron trifluoride diethyl ether solution. The added reaction solvent is one of tetrahydrofuran, 1,4-dioxane and N,N-dimethylformamide. The molar ratio of compound I to the reducing agent is 1:3.0-5.0.

[0032] As a further description of the above technical solution:

[0033] The oxidant used in step four is one of sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, potassium hypobromite, and calcium hypobromite; the molar ratio of compound III to the oxidant is 1:1.0-3.0; a reaction catalyst, a reaction solvent, and a base are added in step four; the reaction catalyst is one of potassium bromide, sodium bromide, and lithium bromide; the reaction solvent is one of dichloromethane, trichloromethane, and tetrahydrofuran; the volume ratio of compound III to the reaction solvent is 1:5-20; the base is one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate; and the reaction temperature of the oxidation reaction is -20 to 10℃.

[0034] As a further description of the above technical solution:

[0035] The preparation method of compound II includes the following steps:

[0036]

[0037] Step A1: Add 50g of compound I, 49g of ethylamine hydrochloride, and 400mL of dichloromethane to the reaction flask, and cool the compound I, ethylamine hydrochloride, and dichloromethane to 10-20℃ and stir to mix.

[0038] Step A2: Then slowly add 77.8g of N,N-diisopropylethylamine, cool to below 30℃, then add 44.7g of 1-hydroxybenzotriazole and 63.4g of 1-ethyl-3-carbodiimide, cool to 20-30℃ and stir to react for 2-3 hours;

[0039] Step A3: Add 600 mL of 10% sodium carbonate solution in three portions and wash three times to remove the organic layer. Adjust the pH to 1 and filter to remove HOBt solids to obtain the filtrate.

[0040] Step A4: Add 200 mL of ethyl acetate to the filtrate and extract three times. Add anhydrous sodium sulfate to the organic layer, dry and filter. Elute with ethyl acetate, evaporate the filtrate to dryness, and desorb once with 50 mL of methyl tert-butyl ether.

[0041] Step A5: Add 100 mL of tetrahydrofuran and stir to reflux until dissolved. After dissolution, add 300 mL of methyl tert-butyl ether and keep warm for 0.5 h. Use a step cooling method until a solid precipitates and keep warm for 0.5 h. Continue to cool step by step to 0-10 °C and keep warm for 0.5-1 h. Filter and wash with methyl tert-butyl ether. Place the obtained solid in an environment of 50 °C and dry for 12 h to obtain 51.1 g of white solid compound II.

[0042] As a further description of the above technical solution:

[0043] The preparation method of compound V includes the following steps:

[0044]

[0045] Step B1: Add 45g of compound IV hydrochloride, 250mL of dichloromethane, and 44.2g of sodium carbonate to the reaction flask, cool to 0-10℃ and stir to mix, then add 47.7g of Boc anhydride dropwise and keep the temperature at 20-30℃ for 2-3 hours.

[0046] Step B2: After the reaction of the raw materials was detected by high performance liquid chromatography, the solution was filtered to remove salt and the filtrate was washed twice with 100 mL of water. Anhydrous sodium sulfate was added to the filtrate and dried. The solution was concentrated under reduced pressure to obtain 58 g of oily compound V.

[0047] As a further description of the above technical solution:

[0048] The preparation method of compound III includes the following steps:

[0049]

[0050] Step C1: Add 400 mL of dichloromethane, 50 g of compound V, 2.8 g of 2,2,6,6-tetramethylpiperidine-1-oxy radical, 30 g of sodium bicarbonate and 1.56 g of lithium bromide to the reaction flask, stir and cool to -10-0℃;

[0051] Step C2: After cooling, add 170g of 10% sodium hypochlorite dropwise, cool to -10-0℃ and keep warm for 1-2 hours to react the raw materials;

[0052] Step C3: After the raw materials have reacted completely, add 0.5g of sodium sulfite and stir for 15-30 minutes to remove oxidizing properties. Stir and heat to 10-20℃ and filter. Rinse the filter cake with 50mL of water, dry it, and add 100mL of dichloromethane to the organic layer and stir to wash it once. Remove the water layer after separation, combine the organic layers, and add 100mL of water to the organic layer to wash it once.

[0053] Step C4: Concentrate and dry the organic layer under reduced pressure, then add 100 mL of tetrahydrofuran and 200 mL of saturated sodium bisulfite solution and stir for 30 min. After stirring, the layers will separate into a lower aqueous layer and an organic layer. Set the lower aqueous layer aside for later use. Add 100 mL of saturated sodium bisulfite to the organic layer and stir for 30 min. Then separate the organic layer into an aqueous layer. Combine the lower aqueous layer and the aqueous layer, and repeat three times.

[0054] Step C5: Remove the organic layer, add 200 mL of methyl tert-butyl ether to the aqueous layer, stir to extract and remove the organic layer, add 50% sodium hydroxide dropwise to the aqueous layer to adjust the pH to 8.5-9.5, then filter to remove salt, add 200 mL of methyl tert-butyl ether to the filtrate and stir to extract, dry the organic layer with anhydrous sodium sulfate, filter to obtain the filtrate, concentrate the filtrate to obtain 37 g of colorless oily compound III.

[0055] Compared with the prior art, the present invention has the following beneficial effects:

[0056] This invention proposes a novel, low-cost synthetic route for key intermediates of ellaxizone suitable for large-scale industrial production. The route comprises four steps: first, compound I is condensed with ethylamine to obtain compound II; then, compound II is reduced to compound IV; next, a protecting group is added to compound IV to form compound V; finally, the final target product, compound III, is prepared via oxidation. The entire process employs relatively mild reaction conditions and does not involve ultra-low temperatures or highly hazardous chemical reagents, significantly reducing production costs and safety risks.

[0057] Furthermore, in the first condensation reaction, a variety of common condensing agents and additives were selected, making the reaction more flexible and controllable. The second reduction reaction used relatively conventional and easily handled reducing agents such as sodium borohydride. In the third step of adding protecting groups, the selected protecting groups not only effectively protected the target functional groups from subsequent reactions but also facilitated their removal in later steps. In the final oxidation reaction, sodium hypochlorite was preferred as the oxidant, and it was used in conjunction with catalysts such as potassium bromide to achieve efficient oxidation at lower temperatures, reducing the possibility of byproduct formation. Attached Figure Description

[0058] Figure 1 This is a schematic diagram of the hydrogen NMR spectrum of compound III of the present invention;

[0059] Figure 2 This is a schematic diagram of the IIIHPLC purity detection of the compound of the present invention. Detailed Implementation

[0060] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0061] Example 1:

[0062] Please see Figure 1-2 This invention provides a technical solution: a method for synthesizing an alasin intermediate, the method comprising the following steps:

[0063]

[0064] Step 1: Compound I is condensed with ethylamine to obtain compound II;

[0065] Step 2: Reduce compound II to obtain compound IV;

[0066] Step 3: Remove the protecting group from compound IV to obtain compound V, wherein R in compound V is one of Boc, Cbz, or Fmoc;

[0067] Step 4: Oxidize compound V to obtain compound III.

[0068] This paper presents a novel, low-cost synthetic route for key intermediates of ellaxizone suitable for large-scale industrial production. The route comprises four steps: first, compound I is condensed with ethylamine to obtain compound II; then, compound II is reduced to compound IV; next, a protecting group is added to compound IV to form compound V; finally, the final target product, compound III, is prepared through an oxidation reaction. The entire process employs relatively mild reaction conditions, avoiding ultra-low temperatures or highly hazardous chemical reagents, significantly reducing production costs and safety risks. Furthermore, in the first condensation reaction, various common condensing agents and additives were selected, making the reaction more flexible and controllable. The second reduction reaction utilizes conventional and easily handled reducing agents such as sodium borohydride. In the third step, the addition of the protecting group effectively protects the target functional group from subsequent reactions and facilitates its removal in later steps. In the final oxidation reaction, sodium hypochlorite is preferred as the oxidant, and potassium bromide and other catalysts are used to achieve efficient oxidation at lower temperatures, reducing the possibility of byproduct formation.

[0069] Example 2:

[0070] In step one, the condensation reaction of compound I with ethylamine uses one of the following condensing agents: dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU). The added condensation additive is one of 1-hydroxybenzotriazole (HOBT) and 1-hydroxy-7-azabenzotriazole (HOAT). The molar ratio of compound I to the condensing agent is 1:1.0-3.0, preferably 1.05 eq; the molar ratio of compound II to the condensing additive is 1:1.0-3.0, preferably 1.1 eq; the ethylamine is one of ethylamine hydrochloride, ethylamine methanol solution, and ethylamine aqueous solution, preferably ethylamine hydrochloride; the reaction solvent for the condensation reaction is one of dichloromethane, trichloromethane, tetrahydrofuran, methanol, and ethanol, preferably dichloromethane; the reaction temperature is 10-35℃, preferably 20-30℃.

[0071] The reducing agent selected in step two is one of sodium borohydride, iodine system, borane-THF solution, and boron trifluoride diethyl ether solution. The added reaction solvent is one of tetrahydrofuran, 1,4-dioxane, and N,N-dimethylformamide, preferably tetrahydrofuran. The molar ratio of compound I to the reducing agent is 1:3.0-5.0, preferably 3.0 eq.

[0072] The oxidant used in step four is one of sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, potassium hypobromite, and calcium hypobromite, preferably sodium hypochlorite; the molar ratio of compound III to the oxidant is 1:1.0-3.0; in step four, a reaction catalyst, a reaction solvent, and a base are added to accelerate the reaction rate. The reaction catalyst is one of potassium bromide, sodium bromide, and lithium bromide, preferably potassium bromide; the reaction solvent is one of dichloromethane, trichloromethane, and tetrahydrofuran, preferably dichloromethane; the volume ratio of compound III to the reaction solvent is 1:5-20, preferably 1:8; the base is one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate, preferably sodium bicarbonate; the reaction temperature of the oxidation reaction is -20-10℃, preferably -10-0℃.

[0073] Example 3:

[0074] The preparation method of compound II includes the following steps:

[0075]

[0076] Step A1: Add 50g of compound I, 49g of ethylamine hydrochloride, and 400mL of dichloromethane to the reaction flask, and cool the compound I, ethylamine hydrochloride, and dichloromethane to 10-20℃ and stir to mix.

[0077] Step A2: Then slowly add 77.8g of N,N-diisopropylethylamine, cool to below 30℃, then add 44.7g of 1-hydroxybenzotriazole and 63.4g of 1-ethyl-3-carbodiimide, cool to 20-30℃ and stir to react for 2-3 hours;

[0078] Step A3: Add 600 mL of 10% sodium carbonate solution in three portions and wash three times to remove the organic layer. Adjust the pH to 1 and filter to remove HOBt solids to obtain the filtrate.

[0079] Step A4: Add 200 mL of ethyl acetate to the filtrate and extract three times. Add anhydrous sodium sulfate to the organic layer, dry and filter. Elute with ethyl acetate, evaporate the filtrate to dryness, and desorb once with 50 mL of methyl tert-butyl ether.

[0080] Step A5: Add 100 mL of tetrahydrofuran and stir to reflux until dissolved. After dissolution, add 300 mL of methyl tert-butyl ether and keep warm for 0.5 h. Use a step cooling method until a solid precipitates and keep warm for 0.5 h. Continue to cool step by step to 0-10 °C and keep warm for 0.5-1 h. Filter and wash with methyl tert-butyl ether. Place the obtained solid in an environment of 50 °C and dry for 12 h to obtain 51.1 g of white solid compound II.

[0081] The preparation method of compound V includes the following steps:

[0082]

[0083] Step B1: Add 45g of compound IV hydrochloride, 250mL of dichloromethane, and 44.2g of sodium carbonate to the reaction flask, cool to 0-10℃ and stir to mix, then add 47.7g of Boc anhydride dropwise and keep the temperature at 20-30℃ for 2-3 hours.

[0084] Step B2: After the reaction of the raw materials was detected by high performance liquid chromatography, the solution was filtered to remove salt and the filtrate was washed twice with 100 mL of water. Anhydrous sodium sulfate was added to the filtrate and dried. The solution was concentrated under reduced pressure to obtain 58 g of oily compound V.

[0085] The preparation method of compound III includes the following steps:

[0086]

[0087] Step C1: Add 400 mL of dichloromethane, 50 g of compound V, 2.8 g of 2,2,6,6-tetramethylpiperidine-1-oxy radical, 30 g of sodium bicarbonate and 1.56 g of lithium bromide to the reaction flask, stir and cool to -10-0℃;

[0088] Step C2: After cooling, add 170g of 10% sodium hypochlorite dropwise, cool to -10-0℃ and keep warm for 1-2 hours to react the raw materials;

[0089] Step C3: After the raw materials have reacted completely, add 0.5g of sodium sulfite and stir for 15-30 minutes to remove oxidizing properties. Stir and heat to 10-20℃ and filter. Rinse the filter cake with 50mL of water, dry it, and add 100mL of dichloromethane to the organic layer and stir to wash it once. Remove the water layer after separation, combine the organic layers, and add 100mL of water to the organic layer to wash it once.

[0090] Step C4: Concentrate and dry the organic layer under reduced pressure, then add 100 mL of tetrahydrofuran and 200 mL of saturated sodium bisulfite solution and stir for 30 min. After stirring, the layers will separate into a lower aqueous layer and an organic layer. Set the lower aqueous layer aside for later use. Add 100 mL of saturated sodium bisulfite to the organic layer and stir for 30 min. Then separate the organic layer into an aqueous layer. Combine the lower aqueous layer and the aqueous layer, and repeat three times.

[0091] Step C5: Remove the organic layer, add 200 mL of methyl tert-butyl ether to the aqueous layer, stir and extract to remove the organic layer, add 50% sodium hydroxide dropwise to the aqueous layer to adjust the pH to 8.5-9.5, then filter to remove salt, add 200 mL of methyl tert-butyl ether to the filtrate and stir to extract, dry the organic layer with anhydrous sodium sulfate, filter to obtain the filtrate, concentrate the filtrate to obtain 37 g of colorless oily compound III, the NMR data of compound III are MS (ESI) m / z = 300 [M+Na]+; 1H NMR (400MHz, CDCl3) δ9.98 (s, 1H), 7.81 (d, J = 7.7Hz, 2H), 7.36 (s, 2H), 3.42 (t, J = 7.4Hz, 2H), 3.14 (d, J = 26.8Hz, 2H), 2.91 (t, J = 7.7Hz, 2H), 1.44 (s, 9H), 1.08 (t, J = 7.1Hz, 3H).

[0092] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing an ellagic group intermediate, characterized in that: The method for synthesizing an alasin intermediate includes the following steps: Step 1: Compound I is condensed with ethylamine to obtain compound II; Step 2: Reduce compound II to obtain compound IV; Step 3: Remove the protecting group from compound IV to obtain compound V, wherein R in compound V is one of Boc, Cbz, or Fmoc; Step 4: Oxidize compound V to obtain compound III.

2. The method for synthesizing an alasin intermediate according to claim 1, characterized in that: In step one, the condensation agent used for the condensation reaction of compound I with ethylamine is one of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI), and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU). The added condensation additive is one of 1-hydroxybenzotriazole (HOBT) and 1-hydroxy-7-azabenzotriazole (HOAT). The molar ratio of compound II to the condensation agent is 1:1.0-3.0, and the molar ratio of compound II to the condensation additive is 1:1.0-3.

0. The ethylamine is one of ethylamine hydrochloride, ethylamine methanol solution, and ethylamine aqueous solution. The reaction solvent for the condensation reaction is one of dichloromethane, trichloromethane, tetrahydrofuran, methanol, and ethanol. The reaction temperature is 10-35℃, preferably 20-30℃.

3. The method for synthesizing an alasin intermediate according to claim 2, characterized in that: The reducing agent selected in step two is one of sodium borohydride, iodine system, borane-THF solution and boron trifluoride diethyl ether solution. The added reaction solvent is one of tetrahydrofuran, 1,4-dioxane and N,N-dimethylformamide. The molar ratio of compound I to the reducing agent is 1:3.0-5.

0.

4. The method for synthesizing an alasin intermediate according to claim 3, characterized in that: The oxidant used in step four is one of sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, potassium hypobromite, and calcium hypobromite. The molar ratio of compound III to the oxidant is 1:1.0-3.

0. In step four, a reaction catalyst, a reaction solvent, and a base are added. The reaction catalyst is one of potassium bromide, sodium bromide, and lithium bromide. The reaction solvent is one of dichloromethane, trichloromethane, and tetrahydrofuran. The volume ratio of compound III to the reaction solvent is 1:5-20. The base is one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate. The reaction temperature of the oxidation reaction is -20 to 10°C.

5. The method for synthesizing an alasin intermediate according to claim 4, characterized in that: The preparation method of compound II includes the following steps: Step A1: Add 50g of compound I, 49g of ethylamine hydrochloride, and 400mL of dichloromethane to the reaction flask, and cool the compound I, ethylamine hydrochloride, and dichloromethane to 10-20℃ and stir to mix. Step A2: Then slowly add 77.8g of N,N-diisopropylethylamine, cool to below 30℃, then add 44.7g of 1-hydroxybenzotriazole and 63.4g of 1-ethyl-3-carbodiimide, cool to 20-30℃ and stir to react for 2-3 hours; Step A3: Add 600 mL of 10% sodium carbonate solution in three portions and wash three times to remove the organic layer. Adjust the pH to 1 and filter to remove HOBt solids to obtain the filtrate. Step A4: Add 200 mL of ethyl acetate to the filtrate and extract three times. Add anhydrous sodium sulfate to the organic layer, dry and filter. Elute with ethyl acetate, evaporate the filtrate to dryness, and desorb once with 50 mL of methyl tert-butyl ether. Step A5: Add 100 mL of tetrahydrofuran and stir to reflux until dissolved. After dissolution, add 300 mL of methyl tert-butyl ether and keep warm for 0.5 h. Use a step cooling method until a solid precipitates and keep warm for 0.5 h. Continue to cool step by step to 0-10 °C and keep warm for 0.5-1 h. Filter and wash with methyl tert-butyl ether. Place the obtained solid in an environment of 50 °C and dry for 12 h to obtain 51.1 g of white solid compound II.

6. The method for synthesizing an alasin intermediate according to claim 5, characterized in that: The preparation method of compound V includes the following steps: Step B1: Add 45g of compound IV hydrochloride, 250mL of dichloromethane, and 44.2g of sodium carbonate to the reaction flask, cool to 0-10℃ and stir to mix, then add 47.7g of Boc anhydride dropwise and keep the temperature at 20-30℃ for 2-3 hours. Step B2: After the reaction of the raw materials was detected by high performance liquid chromatography, the solution was filtered to remove salt and the filtrate was washed twice with 100 mL of water. Anhydrous sodium sulfate was added to the filtrate and dried. The solution was concentrated under reduced pressure to obtain 58 g of oily compound V.

7. The method for synthesizing an alasin intermediate according to claim 6, characterized in that: The preparation method of compound III includes the following steps: Step C1: Add 400 mL of dichloromethane, 50 g of compound V, 2.8 g of 2,2,6,6-tetramethylpiperidine-1-oxy radical, 30 g of sodium bicarbonate and 1.56 g of lithium bromide to the reaction flask, stir and cool to -10-0℃; Step C2: After cooling, add 170g of 10% sodium hypochlorite dropwise, cool to -10-0℃ and keep warm for 1-2 hours to react the raw materials; Step C3: After the raw materials have reacted completely, add 0.5g of sodium sulfite and stir for 15-30 minutes to remove oxidizing properties. Stir and heat to 10-20℃ and filter. Rinse the filter cake with 50mL of water, dry it, and add 100mL of dichloromethane to the organic layer and stir to wash it once. Remove the water layer after separation, combine the organic layers, and add 100mL of water to the organic layer to wash it once. Step C4: Concentrate and dry the organic layer under reduced pressure, then add 100 mL of tetrahydrofuran and 200 mL of saturated sodium bisulfite solution and stir for 30 min. After stirring, the layers will separate into a lower aqueous layer and an organic layer. Set the lower aqueous layer aside for later use. Add 100 mL of saturated sodium bisulfite to the organic layer and stir for 30 min. Then separate the organic layer into an aqueous layer. Combine the lower aqueous layer and the aqueous layer, and repeat three times. Step C5: Remove the organic layer, add 200 mL of methyl tert-butyl ether to the aqueous layer, stir to extract and remove the organic layer, add 50% sodium hydroxide dropwise to the aqueous layer to adjust the pH to 8.5-9.5, then filter to remove salt, add 200 mL of methyl tert-butyl ether to the filtrate and stir to extract, dry the organic layer with anhydrous sodium sulfate, filter to obtain the filtrate, concentrate the filtrate to obtain 37 g of colorless oily compound III.

Images