Process for the preparation of moveltion and intermediates

Abstract

The application discloses a preparation method of moveltion and an intermediate, and belongs to the technical field of medicine preparation. The method is characterized in that a key intermediate is prepared by reacting 3-halogenated methyl benzoic acid or 3-halogenated methyl benzoate as a starting material, and then the substituent of the intermediate and a nitrogen protection group are removed to obtain moveltion. The method has the advantages of short process route, high yield, reduced total cost, mild reaction condition, simple post-treatment and suitability for industrial production. The yield of the prepared moveltion reaches 47%, and the purity is more than 99%.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical preparation technology, and in particular relates to a method for preparing movaporine and its intermediates. Background Technology

[0002] MovapalIn is an LP(a) inhibitor developed by Eli Lilly and Company. Its mechanism of action is to inhibit the formation of Lp(a) and reduce its level by blocking the initial interaction between apolipoprotein(a) and apolipoprotein B, thereby reducing the risk of atherosclerosis and cardiovascular events. It is used to treat adult patients with elevated Lp(a) levels who have been diagnosed with cardiovascular disease or have an increased risk of their first cardiovascular event.

[0003] Patent WO2020247429A1 discloses two methods for synthesizing movaperin; the synthetic route of the first method is as follows:

[0004]

[0005] In the above synthetic route, starting with (S)-3-(3-bromophenyl)-2-[(R)-1-Boc-3-pyrrolyl] tert-butyl propionate (compound 1), compound 2 was obtained through a carbonylation reaction. Compound 2 was then reduced and aminationd to obtain compound 3. Compound 3 was then reduced and aminationd with compound 2 to obtain compound 4. Compound 4 was then acid-hydrolyzed to obtain movaperin. The overall yield of this preparation method was 45%.

[0006] The synthetic route for the second method is as follows:

[0007]

[0008] The second method is similar to the first method, except that in the second method, compound 2 is reacted with hydroxylamine to obtain compound 5 by Ni-catalyzed hydrogenation. Compound 5 is then reductively aminationed with compound 2 and purified by column chromatography to obtain compound 3. Compound 3 is then reduced with compound 2 and purified by column chromatography to obtain compound 4. Finally, it is deprotected by acid hydrolysis to obtain movaporine. The overall yield of this preparation method is 25%.

[0009] The above preparation methods have the following problems: 1. Both preparation methods use (S)-3-(3-bromophenyl)-2-[(R)-1-Boc-3-pyrrolyl]tert-butyl propionate as the starting material, which is expensive. Introducing the expensive starting material into the structure early will result in losses in each reaction step. The expensive starting material has a low atomic conversion rate, which leads to a high material cost for movaperin; 2. The reaction to prepare compound 2 is a high-pressure reaction that needs to be carried out in a high-pressure reactor, while using palladium acetate and carbon monoxide / hydrogen. These reagents and equipment are extremely dangerous; 3. Compounds 2, 3, and 4 in the literature process are all oily substances, which all need to be purified by column chromatography, which is not conducive to industrial scale-up. Summary of the Invention

[0010] The purpose of this application is to provide a method for preparing movaperin and intermediates, and to solve the technical problems in the existing movaperin production process, such as high cost and high loss of starting materials, resulting in high production costs, low conversion rate of synthetic route, low product yield, complex post-processing, and unfavorable large-scale industrialization.

[0011] To achieve the above objectives, the technical solution adopted in this application is: to provide an intermediate for preparing movaperil, the chemical structural formula of which is as follows:

[0012]

[0013] Intermediate II,

[0014] Wherein, the substituent R is one of the following structural formulas.

[0015]

[0016] The nitrogen protecting group P is either a Boc protecting group or a Cbz protecting group.

[0017] This application also provides a method for preparing a movaperin intermediate, the synthesis method is as follows: intermediate III and intermediate IV are coupled in a solvent under strong base catalysis, and then post-processed to obtain intermediate II;

[0018] The structural formulas of intermediates III and IV are as follows:

[0019]

[0020] In one embodiment,

[0021] In intermediate III, the substituent Z is one of Cl, Br, I, TsO, MsO, and TfO; in intermediate IV, the nitrogen protecting group P is a Boc protecting group or a Cbz protecting group; the substituent R is one of the following structural formulas:

[0022]

[0023] In one embodiment,

[0024] The synthetic route for intermediate III is as follows:

[0025]

[0026] In one embodiment,

[0027] Substituent X is one of Cl, Br, I, TsO, MsO or TfO, and substituent Y is one of CH3CH2O, CH3O, OH or H;

[0028] In step a, the NH3 source is one of ammonia methanol, ammonia ethanol, or ammonia water; the molar ratio of compound VII to the NH3 source is 1:3.0-20, preferably 1:10-12; the solvent is one of tetrahydrofuran, methyltetrahydrofuran, acetonitrile, or toluene, preferably tetrahydrofuran and methyltetrahydrofuran; the base is one of n-butylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, or potassium carbonate, preferably triethylamine, sodium carbonate, or potassium carbonate; the reaction temperature is 0-80 ℃, preferably 60-80 ℃.

[0029] In step b, the reducing agent is one of potassium borohydride, sodium borohydride, lithium borohydride, sodium borohydride acetate, potassium borohydride acetate, sodium cyanoborohydride, and potassium cyanoborohydride, preferably potassium borohydride. When using the above reducing agents, the reduction temperature is 60-80 ℃; when the reducing agent is lithium aluminum hydride, the reduction temperature is 0-20 ℃. The solvent used is one of tetrahydrofuran, methyltetrahydrofuran, or toluene, preferably tetrahydrofuran. The amount of solvent used is 3-8 times the volume of intermediate VI, preferably 4-5 times. The molar ratio of intermediate VI to reducing agent is 1:3.1-4.0, preferably 1:3.3-3.6.

[0030] In step c, the halogenating reagent used is one of phosphorus tribromide, hydrobromic acid, thionyl bromide, thionyl chloride, phosphorus oxychloride, oxaloyl chloride, or hydroiodic acid, preferably phosphorus tribromide and hydrobromic acid; the sulfonation reagent used is one of methanesulfonyl chloride, p-toluenesulfonyl chloride, or trifluoromethanesulfonyl chloride, preferably p-toluenesulfonyl chloride.

[0031] Tribenzylamine intermediate III is synthesized from compound VII through a three-step reaction. The three-step reaction has a high conversion rate, and the intermediate is not purified. Intermediate III is obtained by recrystallization. Due to the low price of compound VII, the price of intermediate III obtained in three steps is only 1 / 3 to 1 / 5 of that of intermediate IV. In addition, the overall reaction steps are short, which reduces the raw material cost of this process by more than 40% compared with the original process.

[0032] In one embodiment,

[0033] In the preparation process of intermediate II, the solvent is one of tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, and toluene; preferably, the solvent is tetrahydrofuran, methyltetrahydrofuran, and toluene; the strong base is one of diisopropylaminolithium, diisopropylaminosodium, bis(trimethylsilyl)aminolithium, or bis(trimethylsilyl)aminosodium; preferably, the strong base is diisopropylaminolithium and bis(trimethylsilyl)aminolithium; the molar ratio of intermediate III to the strong base is 1:3.2-4.0, preferably 1:3.4-3.6; the molar ratio of intermediate III to intermediate IV is 1:3.1-3.6, preferably 1:3.2-3.3.

[0034] In one embodiment,

[0035] The coupling reaction occurs at temperatures ranging from -50 to 0 ℃.

[0036] This application also provides a method for preparing movaporine, which specifically includes the following steps: removing the substituent R and nitrogen protecting group P from intermediate II, and then performing post-treatment to obtain movaporine.

[0037] In one embodiment,

[0038] The substituent R and nitrogen protecting group P of intermediate II are removed by a stepwise method, specifically: first, the substituent R is removed under basic conditions, and then the nitrogen protecting group P is removed under acidic conditions.

[0039] The alkaline conditions are a mixture of alkali metal hydroxide and hydrogen peroxide, wherein the alkali metal hydroxide is one of lithium hydroxide, sodium hydroxide, and potassium hydroxide, such as lithium hydroxide / hydrogen peroxide, sodium hydroxide / hydrogen peroxide, or potassium hydroxide / hydrogen peroxide, preferably lithium hydroxide / hydrogen peroxide; the molar ratio of intermediate II, alkali metal hydroxide, and hydrogen peroxide is 1:3.6-5.0:3.6-5.0, and the reaction temperature is 0-20 ℃; the acidic conditions are one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, preferably hydrochloric acid and trifluoroacetic acid, and the reaction temperature is 60-80 ℃.

[0040] In one embodiment,

[0041] The substituent R and nitrogen protecting group P of intermediate II are removed by a one-pot method, specifically by using a strong acid aqueous solution at a temperature of 90-120 °C to simultaneously remove the substituent R and nitrogen protecting group P.

[0042] The strong acid aqueous solution is one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid, preferably hydrochloric acid, sulfuric acid, or trifluoroacetic acid;

[0043] The one-pot method uses water as the solvent, and the amount of solvent is 5-10 times the volume of intermediate II; preferably 7-8 times.

[0044] In one embodiment,

[0045] The synthetic routes of intermediate III, intermediate II, and movapeline are combined to form a method for preparing movapeline intermediate and movapeline, specifically including the following steps:

[0046] (a) In a solvent, compound VII is the starting material and undergoes a nucleophilic substitution reaction with ammonia in the presence of a base, followed by post-processing to obtain intermediate VI;

[0047] (b) In a solvent, under the action of a reducing agent, intermediate VI undergoes a reduction reaction, and then is post-processed to obtain intermediate V;

[0048] (c) In a solvent, intermediate V undergoes a nucleophilic substitution reaction in the presence of a halogenating agent or a sulfonating agent, and is then post-treated to obtain intermediate III;

[0049] (d) Intermediate III undergoes a coupling reaction with intermediate IV under the action of a strong base, and then undergoes post-processing to obtain intermediate II;

[0050] (e) Intermediate II is desubstituent R and nitrogen protecting group P, and then post-processed to obtain the final product movaporine. The reaction route is as follows:

[0051]

[0052] This application provides a method for preparing movapeline and its intermediates, simplifying the synthetic route of movapeline and reducing production costs. The core of the method lies in first synthesizing tribenzylamine intermediate III, then condensing it with the expensive intermediate IV, attaching three chiral fragments at once, and finally removing the substituents and protecting groups all at once. This reduces the entire reaction by three steps, significantly improving conversion efficiency. Based on the expensive intermediate IV, the yield is increased by 10-15% compared to the original process, and the raw material cost is reduced by more than 40%. Intermediates III and IV are both solids and are purified by recrystallization. Finally, intermediate II is purified by column chromatography, deprotected, and crystallized to obtain movapeline. The entire process involves only one column chromatography purification step, significantly simplifying the preparation process and reducing manufacturing costs compared to the original three column chromatography steps. Compared with existing technologies, this method has the following advantages:

[0053] 1. The starting materials of the traditional process are changed to inexpensive commercial intermediates. At the same time, the key intermediates are prepared by one-pot method and recrystallization, avoiding multiple column chromatography operations, which is more suitable for industrial production.

[0054] 2. The preparation of intermediate II avoids the use of palladium on carbon, carbon monoxide and hydrogen, and does not require the use of a high-pressure reactor, which improves production safety and saves production time.

[0055] 3. This process route significantly reduces production costs, with total costs decreasing by more than 40%. Attached Figure Description

[0056] To more clearly illustrate the technical solutions in the embodiments of this application, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of this application. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0057] Figure 1 The LCMS spectrum of intermediate II-1 obtained in Example 1;

[0058] Figure 2 The HNMR spectrum of intermediate II-1 obtained in Example 1;

[0059] Figure 3 The liquid phase spectrum of movaperil obtained in Example 1;

[0060] Figure 4 The LCMS spectrum of movaperil obtained in Example 1;

[0061] Figure 5 The ¹H NMR spectrum of movaperin obtained in Example 1;

[0062] Figure 6 The LCMS spectrum of intermediate VI-2 obtained in Example 5;

[0063] Figure 7 The HNMR spectrum of intermediate VI-2 obtained in Example 5;

[0064] Figure 8 The LCMS spectrum of intermediate V obtained in Example 5;

[0065] Figure 9 The HNMR spectrum of intermediate V obtained in Example 5;

[0066] Figure 10 The LCMS spectrum of intermediate III-2 obtained in Example 5;

[0067] Figure 11 The image shows the HNMR spectrum of intermediate Ⅲ-2 obtained in Example 5. Detailed Implementation

[0068] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, this application will be further described in detail. It should be understood that the specific embodiments described herein are only for explaining this application and are not intended to limit this application.

[0069] Example 1

[0070] A method for synthesizing movaperin, with the following reaction equation:

[0071]

[0072] Preparation of intermediate II-1:

[0073] Add 15.85 g of intermediate IV-1 (41.0 mmol, 3.3 eq) and 50 mL of THF to a 250 mL four-necked flask. Cool to -60 to -50 °C, and add 44.5 mL of a THF solution of bis(trimethylsilyl)aminolithium (1 mol / L, 44.5 mmol, 3.6 eq) dropwise between -50 and -30 °C. Stir for 0.5–1 h, then add 50 mL of a THF solution of intermediate III-2 (7.00 g, 12.4 mmol, 1.0 eq). Heat the reaction mixture to 0 °C and stir for 5 h. After the reaction is complete, adjust the pH of the solution to 6–7 with a saturated ammonium chloride aqueous solution to quench the reaction mixture. Extract with 100 mL of ethyl acetate. Concentrate the organic phase to dryness under reduced pressure. Use silica gel column chromatography with a gradient elution system of ethyl acetate / n-heptane at a volume ratio of 10–50% to purify the residue to obtain 13.25 g of THF. g intermediate II-1, yield 72%; Intermediate II-1 was characterized as follows: Figure 1-2 As shown;

[0074] Preparation of movapeline:

[0075] 12.00 g of intermediate II-1 (8.1 mmol) and 100 mL of hydrochloric acid aqueous solution (6 mol / L) were added to a 250 mL three-necked flask. The reaction was carried out at 90-100 °C for 12 h. The reaction solution was then cooled to 55 °C, and 0.60 g of activated carbon was added and stirred for 1 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to remove hydrochloric acid. 60 mL of anhydrous ethanol was added to dissolve the filtrate, and the pH of the solution was adjusted to 6-7 with triethylamine. The mixture was then kept at 50-60 °C with stirring for 2 h. The mixture was filtered, and the filter cake was washed with 24 mL of anhydrous ethanol and dried under vacuum at 40-50 °C to obtain 4.58 g of movaperine, with a yield of 80%. The movaperine was characterized as follows: Figure 3-5 As shown.

[0076] Example 2

[0077] A method for synthesizing movaperin, with the following reaction equation:

[0078]

[0079] Preparation of intermediate II-12:

[0080] Add 9.63 g of intermediate IV-12 (24.4 mmol, 3.2 eq) and 50 mL of THF to a 100 mL four-necked flask. Cool to -50 to -40 °C, and add 13.0 mL of a THF solution of lithium diisopropylamino (2 mol / L, 25.9 mmol, 3.4 eq) dropwise at -40 to -30 °C. Stir for 2 h, then add 30 mL of a THF solution of intermediate III-1 (3.30 g, 7.6 mmol, 1.0 eq). After the addition is complete, heat to 0-30 °C and stir for 2 h. Adjust the pH of the reaction solution to 6-7 by adding saturated ammonium chloride aqueous solution, then add 100 mL of ethyl acetate for extraction. Concentrate the organic phase to dryness under reduced pressure. Use silica gel column chromatography with ethyl acetate / n-heptane as the elution system, performing gradient elution at a volume ratio of 10-80%. Purify the residue to obtain 8.27 g of THF. g intermediate II-12, yield 70%;

[0081] Preparation of movapeline:

[0082] 7.00 g of intermediate II-12 (4.5 mmol), 50 mL of drinking water, and 40 mL of methanesulfonic acid were added to a 100 mL three-necked flask. The mixture was heated to 90-100 °C and reacted for 12 h. The reaction solution was then cooled to 50 °C, and 0.35 g of activated carbon was added and stirred for 1 h. The mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. 50 mL of methanol was added to dissolve the solid, and the pH of the solution was adjusted to 7 with tri-n-propylamine to precipitate the solid. The mixture was kept at 50-60 °C and stirred for 2 h. The mixture was then filtered, and the filter cake was washed with 15 mL of methanol and dried under vacuum at 40-50 °C to obtain 2.35 g of movaperin, with a yield of 73%.

[0083] Example 3

[0084] A method for synthesizing movaperin, with the following reaction equation:

[0085]

[0086] Preparation of intermediate II-20:

[0087] 11.23 g of intermediate IV-6 (26.3 mmol, 3.3 eq) and 50 mL of THF were added to a 250 mL four-necked flask. The mixture was cooled to -60 to -50 °C, and 28 mL of a THF solution of sodium bis(trimethylsilyl)amino (1 mol / L, 28 mmol, 3.5 eq) was added dropwise at -50 to -40 °C. The mixture was stirred for 1 h, and then 20 mL of a THF solution of intermediate III-4 (6.70 g, 8.0 mmol, 1.0 eq) was added dropwise. After the addition was complete, the mixture was heated to 0-10 °C and stirred for 8 h. The pH of the reaction solution was adjusted to 6-7 by adding saturated ammonium chloride aqueous solution. The solution was then extracted with 100 mL of ethyl acetate. The organic phase was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography using a gradient elution system of ethyl acetate / n-heptane at a volume ratio of 10-60%. 8.82 g of the solution was obtained. g intermediate II-20, yield 69%;

[0088] Preparation of movapeline:

[0089] Add 8.00 g of intermediate II-20 (5.0 mmol) and 60 mL of tetrahydrofuran to a 100 mL three-necked flask, stir until dissolved, and cool to 0-10 °C. Add an aqueous solution prepared with 0.95 g of lithium hydroxide monohydrate (22.5 mmol) and 20 mL of drinking water. Slowly add 2.58 g of 30% hydrogen peroxide (22.5 mmol) at 0-10 °C. After the addition is complete, keep the reaction at this temperature for 2 h. Cool the reaction solution to 10 °C and slowly add saturated sodium sulfite solution to quench excess hydrogen peroxide until the starch-potassium iodide test paper no longer changes color. Concentrate under reduced pressure to obtain the organic phase. Extract the concentrate with 30 mL of ethyl acetate. Adjust the pH of the aqueous phase to 6-7 with glacial acetic acid and extract twice with 50 mL of ethyl acetate. Combine the organic phases and concentrate to obtain 5.48 g of foamy solid. Add 30 mL of drinking water and 30 mL of sulfuric acid to the three-necked flask containing the foamy solid, and heat to 60-65 °C. Stir at ℃ for 2 h, concentrate the reaction solution to dryness under reduced pressure, add 50 mL isopropanol to dissolve, add tri-n-butylamine dropwise to adjust the pH of the solution to 6-7, stir for 2 h after the solid precipitates, filter, wash the filter cake with 20 mL isopropanol, and dry under vacuum at 40-50 ℃ to obtain 2.52 g movaporine, yield 71%.

[0090] Example 4

[0091] A method for preparing intermediate III-1, the reaction equation of which is as follows:

[0092]

[0093] Preparation of intermediate VI-2:

[0094] 10.00 g of compound VII-2 (50.3 mmol, 1.0 eq) and 80 mL of ammonia-ethanol solution (7 mol / L) were added to a 200 mL pressure-resistant flask. The mixture was reacted at 20-30 °C for 3 h. The reaction solution was concentrated under reduced pressure. 80 mL of 2-methyltetrahydrofuran, 25.48 g of triethylamine (251.7 mmol, 5.0 eq), and 12.00 g of compound VII-2 (60.4 mmol, 1.2 eq) were added to the concentrate. The mixture was heated to 70-80 °C and reacted for 12 h. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give 18.40 g of intermediate VI-2, with a yield of 99%.

[0095] Preparation of intermediate V:

[0096] 4.35 g sodium borohydride (114.4 mmol, 3.6 eq), 80 mL toluene, and 16.00 g intermediate VI-2 (31.8 mmol, 1.0 eq) were added to a 100 mL three-necked flask. The mixture was heated to 60 °C and reacted for 5 h. 100 mL of water was added to the reaction solution, and the pH was adjusted to 7-8 with glacial acetic acid. The solution was extracted with 100 mL of ethyl acetate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 11.75 g intermediate V, with a yield of 98%.

[0097] Preparation of intermediate III-1:

[0098] 10.00 g of intermediate V (26.5 mmol, 1.0 eq) and 80 mL of dichloromethane were added to a 250 mL three-necked flask. The mixture was cooled to 5 °C, and 11.35 g of thionyl chloride (95.4 mmol, 3.6 eq) was added dropwise at a controlled temperature of 0-10 °C. The pH of the reaction solution was adjusted to 7-8 by adding saturated sodium carbonate aqueous solution. The solution was extracted with 100 mL of ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was dissolved in 15 mL of ethyl acetate and heated to 50-60 °C for 3 h. The mixture was then cooled to 0-5 °C and filtered. The filter cake was washed with 20 mL of n-heptane and dried under vacuum at 40-50 °C to obtain 10.09 g of intermediate III-1, with a yield of 88%.

[0099] Example 5

[0100] A method for preparing intermediate III-2, the reaction equation of which is as follows:

[0101]

[0102] Preparation of intermediate VI-2:

[0103] 10.00 g of compound VII-8 (43.7 mmol, 1.0 eq) and 80 mL of ammonia-methanol solution (7 mol / L) were added to a 200 mL pressure-resistant flask. The mixture was reacted at 0–5 °C for 3 h. The reaction solution was concentrated under reduced pressure. 80 mL of tetrahydrofuran, 12.08 g of anhydrous potassium carbonate (87.4 mmol, 2.0 eq), and 12.00 g of compound VII-8 (52.4 mmol, 1.2 eq) were added to the concentrate. The mixture was heated to 60–70 °C and reacted for 8 h. After the reaction was complete, the mixture was filtered. The filter cake was washed with 20 mL of tetrahydrofuran. The combined eluents were concentrated under reduced pressure to give 14.48 g of intermediate VI-2, with a yield of 98%. Intermediate VI-2 was characterized as follows: Figure 6-7 As shown;

[0104] Preparation of intermediate V:

[0105] 5.89 g potassium borohydride (109.2 mmol, 3.6 eq), 60 mL tetrahydrofuran, and 14.00 g intermediate VI-2 (30.3 mmol, 1.0 eq) were added to a 100 mL three-necked flask. The mixture was heated to 65 °C and reacted for 5 h. The pH of the reaction solution was adjusted to 7-8 by adding 1 mol / L hydrochloric acid aqueous solution. The solution was extracted with 100 mL ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 11.11 g intermediate V, with a yield of 97%. Intermediate V was characterized as follows: Figure 8-9 As shown;

[0106] Preparation of intermediate III-2:

[0107] 10.00 g of intermediate V (26.5 mmol, 1.0 eq) and 80 mL of dichloromethane were added to a 250 mL three-necked flask. The mixture was cooled to 0 °C, and 25.80 g of phosphorus tribromide (95.4 mmol, 3.6 eq) was added dropwise at a controlled temperature of 0-10 °C. The pH of the reaction solution was adjusted to 7-8 by adding saturated sodium carbonate aqueous solution. The mixture was extracted with 100 mL of ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was added to 20 mL of ethyl acetate, and the mixture was heated to 50-60 °C to dissolve it completely. After 2 h, the temperature was lowered to 20-30 °C, and the solid precipitated. The solid was filtered, and the filter cake was washed with 20 mL of n-heptane and dried under vacuum at 40-50 °C to obtain 12.90 g of intermediate III-2, with a yield of 86%. Intermediate III-2 was characterized as follows. Figure 10-11 As shown.

[0108] Example 6

[0109] A method for preparing intermediate III-4, the reaction equation of which is as follows:

[0110]

[0111] Preparation of compound VI-2:

[0112] 10.00 g of compound VII-8 (43.7 mmol, 1.0 eq), 40 mL of methanol, and 40 mL of 25% concentrated ammonia were added to a 200 mL pressure-resistant flask. The mixture was reacted at 0–5 °C for 5 h. The reaction solution was concentrated to dryness under reduced pressure. 80 mL of toluene, 9.28 g of anhydrous sodium carbonate (87.4 mmol, 2.0 eq), and 12.00 g of compound VII-8 (52.4 mmol, 1.2 eq) were added to the concentrate. The mixture was heated to 70–80 °C and reacted for 5 h. After the reaction was complete, the mixture was filtered, and the filter cake was washed with toluene. The eluents were combined and concentrated under reduced pressure to give 14.78 g of intermediate VI-2, with a yield of 100%.

[0113] Preparation of intermediate V:

[0114] 14.00 g of intermediate VI-2 (30.3 mmol, 1.0 eq) and 60 mL of 2-methyltetrahydrofuran were added to a 100 mL three-necked flask. The mixture was cooled to 0 °C, and 4.15 g of lithium aluminum hydride (109.2 mmol, 3.6 eq) was added. The mixture was kept at 0–10 °C for 12 h. The reaction solution was quenched with 100 mL of water, and the pH of the solution was adjusted to 7–8 with 1 mol / L hydrochloric acid aqueous solution. The solution was extracted with 100 mL of ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 11.00 g of intermediate V, with a yield of 96%.

[0115] Preparation of intermediate III-4:

[0116] 10.00 g of intermediate V (26.5 mmol, 1.0 eq) and 80 mL of dichloromethane were added to a 250 mL three-necked flask. The mixture was cooled to 0 °C, and 18.10 g of p-toluenesulfonyl chloride (87.6 mmol, 3.3 eq) was added while maintaining the temperature at 0-10 °C. After the addition was complete, the mixture was heated to room temperature and reacted for 2 h. The pH of the reaction solution was adjusted to 7-8 by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted with 100 mL of ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was dissolved in 20 mL of ethyl acetate and heated to 50-60 °C for 3 h. The mixture was then cooled to 10-20 °C, filtered, and the filter cake was washed with 15 mL of n-heptane. The filter cake was dried under vacuum at 50-60 °C to obtain 18.25 g of intermediate III-4, with a yield of 82%.

[0117] Example 7

[0118] A method for preparing intermediate IV-1, the reaction equation of which is as follows:

[0119]

[0120] Add 10.01 g of (R)-2-(1-Boc-3-pyrrolyl)acetic acid (43.7 mmol, 1.0 eq), 80 mL of tetrahydrofuran, and 13.26 g of triethylamine (131.1 mmol, 3.0 eq) to a 500 mL three-necked flask. Under nitrogen protection, lower the temperature to 0-5 °C, and add 6.85 g of pivaloyl chloride (56.8 mmol, 1.3 eq) at 0-10 °C. After adding the solution, maintain the temperature and stir for 0.5 h. Then, at 0-10 °C, add 2.41 g of lithium chloride (56.8 mmol, 1.3 eq) and 7.74 g of (S)-4-benzyl-2-azolidinone (43.7 mmol, 1.0 eq). Incubate the reaction for 3 h. Quench the reaction with 100 mL of drinking water, and then extract with 100 mL of ethyl acetate. Separate the organic phase using 100 mL of ethyl acetate. Wash with mol / L dilute hydrochloric acid aqueous solution, then wash with 100 mL of 1 mol / L sodium hydroxide aqueous solution. Concentrate the organic phase under reduced pressure. Add 100 mL of n-heptane and 20 mL of ethyl acetate to the residue, heat to 50-60 °C to dissolve, and after 2 h, cool to 10-20 °C. Filter, rinse the filter cake with 20 mL of n-heptane, and dry the filter cake under vacuum at 50-60 °C to obtain 14.60 g of intermediate IV-1, yield 84%.

[0121] Example 8

[0122] A method for preparing intermediate IV-5, the reaction equation of which is as follows:

[0123]

[0124] Intermediate IV-5 was prepared using (R)-2-(1-Boc-3-pyrrolyl)acetic acid and S-camphor flavin lactam according to the steps of Example 7, and the product was purified by recrystallization.

[0125] Example 9

[0126] A method for preparing intermediate IV-12, the reaction equation of which is as follows:

[0127]

[0128] Intermediate IV-12 was prepared using (R)-2-(1-Cbz-3-pyrrolidinyl)acetic acid and (3S)-3-methyl-2,3-dihydro-1λ6-benzo[d][1,2]thiazazacyclopentanone-1,1-dione, following the steps of Example 7. The product was purified by recrystallization to obtain intermediate IV-12.

[0129] The above description is merely a preferred embodiment of this application and is not intended to limit this application. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A method for preparing movaporine, characterized in that, Specifically, the following steps are included: (a) Intermediate III undergoes a coupling reaction with intermediate IV under the action of a strong base, and then is followed up to obtain intermediate II; (b) Intermediate II is desubstituent R and nitrogen protecting group P, and then post-processed to obtain the final product movaporine; the reaction route is as follows: ； In step (a), the molar ratio of intermediate III to the strong base is 1:3.2-4.0, and the molar ratio of intermediate III to intermediate IV is 1:3.1-3.

6. In intermediate III, the substituent Z is one of Cl, Br, I, TsO, MsO, and TfO; in intermediate IV, the nitrogen protecting group P is a Boc protecting group or a Cbz protecting group; and the substituent R is one of the following structural formulas: 。 2. The method for preparing movaporine according to claim 1, characterized in that, The substituent R and nitrogen protecting group P of intermediate II are removed by a stepwise method, specifically: first, the substituent R is removed under basic conditions, and then the nitrogen protecting group P is removed under acidic conditions. The alkaline condition is a mixture of alkali metal hydroxide and hydrogen peroxide, wherein the alkali metal hydroxide is one of lithium hydroxide, sodium hydroxide, or potassium hydroxide, and the molar ratio of intermediate II, alkali metal hydroxide, and hydrogen peroxide is 1:3.6-5.0:3.6-5.0, with a reaction temperature of 0-20 °C; the acid condition is one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, or p-toluenesulfonic acid, with a reaction temperature of 60-80 °C.

3. The method for preparing movaporine according to claim 1, characterized in that, The substituent R and nitrogen protecting group P of intermediate II are removed by a one-pot method, specifically by using a strong acid aqueous solution at a temperature of 90-120 °C to simultaneously remove the substituent R and nitrogen protecting group P. The strong acid aqueous solution is one of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid.

4. The method for preparing movaporine according to claim 1, characterized in that, The coupling reaction in step (a) is carried out at a temperature of -60 to -30 °C.

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