An intermediate compound for preparing ledipasvir and a preparation method and use thereof

Abstract

The application provides an intermediate for preparing lenacapavir and a preparation method and use thereof, and comprises intermediate compound A and intermediate compound B and a preparation method thereof. In the technical scheme provided by the application, a high-quality lenacapavir intermediate can be obtained, without the need for separation and purification by using a silica gel column, without the need for complicated post-treatment operations, the complicated separation and purification steps are avoided, the waste of raw materials is avoided, the production cost is reduced, and the application is more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis, and in particular to an intermediate compound for the preparation of lenakapavir, its preparation method, and its uses. Background Technology

[0002] Lenacapavir, chemical name: ((4-chloro-7-(2-((S-1-(2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropyl[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamido)-2-(3,5-difluorophenyl)ethyl)-6-(3-methylsulfonyl)but-1-yn-1-yl)pyridin-3-yl)-1-(2,2,2-trifluoroethyl)-1H-indazole-3-yl)(methylsulfonyl)amide, molecular formula: C 39 H 32 ClF 10 N7O5S2, molecular weight: 968.28, CAS Registry No.: 2189684-44-2, its chemical structure is as follows:

[0003] .

[0004] Lenapamivir is a novel, long-acting HIV-1 capsid inhibitor that inhibits viral replication at multiple stages of the viral life cycle by interfering with the assembly and disassembly of the viral capsid. Its most significant feature is its ultra-long duration of action, requiring only a subcutaneous injection every six months, representing a revolutionary breakthrough in HIV treatment and prevention. It is primarily used in combination therapy for adults with HIV-1 infection who have developed resistance to multiple drugs. For patients who have experienced multiple treatment failures and complex drug resistance, lenapamivir, in combination with other antiretroviral drugs, can effectively suppress viral load and rebuild immune function. Since its approval for marketing in the US and Europe at the end of 2022, it has maintained a high-end and focused market positioning. The global market size in 2023 was estimated at several hundred million US dollars. While its share in the overall global HIV drug market (approximately 30-40 billion US dollars) is still small, it has rapidly become a focal point in its niche market.

[0005] Lenapavir intermediate compound, chemical name: 2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropane[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetic acid, molecular formula: C 10 H7F5N2O2, molecular weight: 282.17, CAS Registry No.: 1620056-83-8, its chemical structural formula is as follows:

[0006] .

[0007] Existing technical document patent WO2018035359A1 reports the following synthetic route 1 for the intermediate of lenakapavir:

[0008]

[0009] .

[0010] The product synthesized in this route is a racemic mixture, which requires chiral column chromatography for separation. This method is inefficient, costly, and difficult to scale up, making it unsuitable for industrial production.

[0011] Existing technical document patent CN119954778A reports the following synthetic route 2 for the intermediate of lenakapavir:

[0012] .

[0013] This route uses chiral compounds as starting materials, which are expensive. Furthermore, it requires the use of strong bases such as lithium diisopropylaminodimethylamine during the reaction and must be carried out at extremely low temperatures ranging from -90°C to 0°C. This places high demands on the temperature control capabilities, energy consumption, and operational safety of the production equipment. Summary of the Invention

[0014] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide an intermediate compound for the preparation of lenakapavir, a method for its preparation, and its uses, in order to solve the problems of harsh reaction conditions, high cost, difficulty in purification, and unsuitability for large-scale industrial production in the existing methods for preparing lenakapavir.

[0015] To achieve the above and other related objectives, the present invention is obtained through the following technical solution.

[0016] The first aspect of this invention discloses a method for obtaining a compound with the structure of Formula I by bromination with a brominating reagent, wherein the reaction route is as follows:

[0017] .

[0018] Preferably, the reaction medium for the bromination reaction is a first organic solvent, which is one or more selected from N,N-dimethylformamide, toluene, chloroform, dichloromethane, dichloroethane, carbon tetrachloride, or acetonitrile. More preferably, the organic solvent is acetonitrile.

[0019] Preferably, the brominating agent in the bromination reaction is one or more of N-bromosuccinimide (abbreviated as NBS), bromine (abbreviated as Br2), and dibromohydantoin (abbreviated as DBDMH). The brominating agent provides the bromine source for the reaction. More preferably, the brominating agent is DBDMH.

[0020] More preferably, the molar ratio of the brominating reagent to the compound of formula I is (0.5~1):1, such as 0.5:1, 0.6:1, 0.7:1, 0.8:1, 0.9:1, or 1:1. If the molar ratio is too small, the reactants will remain unreacted, leading to incomplete reaction; if the molar ratio is too large, the brominating reagent will remain excessively, causing over-bromination and generating impurities. More preferably, the molar ratio is 0.6:1, under which the yield of the monobrominated product is highest.

[0021] Preferably, the bromination reaction temperature is 60–85°C, such as 60–65°C, 65–70°C, 70–75°C, 75–80°C, or 80–85°C. More preferably, the reaction temperature is 80–85°C. Below 60°C, the reaction is slow, and the reactants do not react completely. Due to the boiling point limitation of the solvent acetonitrile, the maximum reaction temperature is 85°C. If a solvent with a higher boiling point is used, increasing the reaction temperature will increase side reactions and generate impurities.

[0022] Preferably, the bromination reaction takes 14 to 20 hours, such as 14, 14, 16, 16, 18, or 20 hours. More preferably, the reaction time is 16 hours.

[0023] Preferably, the bromination reaction further includes a post-treatment step, which includes quenching, extraction, and concentration. More preferably, the quenching involves adding a saturated sodium sulfite aqueous solution and then neutralizing the system with a potassium carbonate aqueous solution to a pH of 9-10; the extraction involves adding ethyl acetate, stirring, and separating the layers to obtain the organic phase; and the concentration involves vacuum distillation of the organic phase. Those skilled in the art can set specific amounts of saturated sodium sulfite aqueous solution and ethyl acetate based on the actual operations of quenching and extraction, as long as the purpose of quenching to terminate the reaction and the phase separation operation of extraction can be achieved. For example, specifically, the volume of saturated sodium sulfite aqueous solution added for quenching is at least 4 times the volume of the compound of formula I, such as 5, 6, 7, or 8 times; the volume of ethyl acetate added for extraction is at least 10 times the volume of the compound of formula I, such as 12, 14, 16, 18, or 20 times.

[0024] The second aspect of this invention discloses a method for obtaining a compound with the structure shown in Formula II by a substitution reaction with ethyl bromoacetate, as shown in the following reaction route:

[0025] .

[0026] Preferably, the molar ratio of compound II to ethyl bromoacetate is 1:(1-1.5), such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5. If the molar ratio is too small, too much ethyl bromoacetate will remain, increasing reaction costs; if the molar ratio is too large, raw materials will remain, leading to incomplete reaction. A ratio of 1:1.1 is preferred.

[0027] Preferably, the reaction medium for the substitution reaction is a second organic solvent, which is selected from one or more of acetonitrile, dichloromethane (DCM), tetrahydrofuran (THF), and ethanol (EtOH). More preferably, the second organic solvent is acetonitrile.

[0028] Preferably, the reaction system for the substitution reaction further includes a basic auxiliary agent, which is one or more of potassium phosphate, potassium carbonate, sodium carbonate, or cesium carbonate. The basic auxiliary agent provides an alkaline environment for the coupling reaction and neutralizes the hydrobromic acid generated in the reaction. More preferably, the basic auxiliary agent is potassium acetate.

[0029] More preferably, the molar ratio of the alkaline auxiliary agent to the compound of formula II is (1~4):1. For example, it can be 1:1, 2:1, 3:1 or 4:1, preferably 2:1.

[0030] Preferably, the reaction temperature for the substitution reaction is 65–85°C. More preferably, the reaction temperature is 80–85°C. When the reaction temperature is below 75°C, the reaction is slow and the reactants do not react completely; when the reaction temperature is below 65°C, the reaction does not occur. Based on the boiling point limitation of the solvent, the maximum reaction temperature is 85°C. If a solvent with a higher boiling point is used, increasing the reaction temperature will increase side reactions and generate impurities.

[0031] Preferably, the reaction time for the substitution reaction is 4 to 8 hours, such as 4 hours, 5 hours, 6 hours, 7 hours, or 8 hours. More preferably, the reaction time is 6 hours.

[0032] Preferably, the process further includes a post-treatment step after the substitution reaction, which includes washing and concentration. More preferably, water is used as the washing agent, and the volume of water added during the washing operation is at least three times, such as four, five, or six times, the volume of the compound of formula II. Preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0033] A third aspect of this invention discloses an intermediate compound A, the structural formula of which is shown in Formula IV:

[0034] .

[0035] The fourth aspect of this invention discloses a method for preparing intermediate compound A, which involves a Suzuki coupling reaction between a compound with the structure described in Formula III and vinyl borate pinacol ester under metal catalysis to obtain the intermediate compound with the structure described in Formula IV. The reaction route is as follows:

[0036] .

[0037] Preferably, the molar ratio of compound III to pinacol vinylboronic acid in the Suzuki coupling reaction is 1:(1.2~1.5), such as 1:1.2, 1:1.3, 1:1.4 or 1:1.5. More preferably, it is 1:1.2. If the ratio is too small, too much of the compound pinacol vinylboronic acid will remain, resulting in waste of raw materials; if the ratio is too large, the compound III will not react completely, and the yield of the target product will decrease.

[0038] Preferably, the reaction medium for the Suzuki coupling reaction is a third organic solvent, which is one or more of toluene, dioxane, N,N-dimethylformamide, and tetrahydrofuran. More preferably, the organic solvent is toluene.

[0039] Preferably, the Suzuki coupling reaction is carried out under a metal catalyst, which is one or more of bis(diphenylacetone)palladium (abbreviated as Pd(dba)2), tetra(triphenylphosphine)palladium (abbreviated as Pd(PPh3)4), bis(tri-tert-butylphosphine)palladium (abbreviated as Pd(t-Bu3P)2), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (abbreviated as Pd(dppf)Cl2), or a Pd(dppf)Cl2 dichloromethane complex. More preferably, the metal catalyst is Pd(dppf)Cl2.

[0040] Preferably, the molar ratio of the metal catalyst to the compound of formula III is (0.001~0.1):1. The amount of catalyst used is the catalytically effective amount. If the amount of catalyst is too small, the reaction will be very slow and the raw material conversion will be insufficient; if the amount of catalyst is too large, the reaction cost will increase. Therefore, considering the reaction rate, reaction conversion rate and reaction cost, more preferably, the molar ratio is (0.025~0.05):1, such as 0.025:1, 0.03:1, 0.035:1, 0.04:1, 0.045:1 or 0.05:1. More preferably, the molar ratio is 0.025:1.

[0041] Preferably, the reaction system of the Suzuki coupling reaction further includes a basic auxiliary agent, which is sodium bicarbonate, potassium carbonate, sodium carbonate, sodium acetate, or potassium acetate. The role of the basic auxiliary agent in the Suzuki coupling reaction is to provide an alkaline environment and neutralize the hydrobromic acid generated in the reaction. More preferably, the basic auxiliary agent is potassium acetate.

[0042] More preferably, the molar ratio of the alkaline auxiliary agent to the compound of formula III is (2~4):1. For example, it can be 2:1, 3:1, or 4:1. Preferably, it is 3:1. If the molar ratio is too large, the system becomes viscous, increasing the difficulty of stirring and easily causing insufficient stirring, preventing the raw materials from fully contacting and reacting. If the molar ratio is too small, the alkalinity in the reaction system is insufficient, failing to completely neutralize the hydrobromic acid generated in the reaction, leading to the reaction stopping midway.

[0043] Preferably, the reaction temperature of the Suzuki coupling reaction is 100–110°C, such as 100°C, 105°C, or 110°C. More preferably, the reaction temperature is 100–105°C. If the reaction temperature is too low (e.g., 80°C), the reaction will not occur; if the reaction temperature is below 100°C, the reaction is very slow and will stop after a period of time, resulting in an incomplete reaction; due to the boiling point limitation of the solvent, the maximum reaction temperature is 110°C. If a solvent with a higher boiling point is used, increasing the reaction temperature will increase side reactions and generate impurities.

[0044] Preferably, the reaction time of the Suzuki coupling reaction is 20-25 hours, such as 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or 25 hours. More preferably, the reaction time is 22 hours.

[0045] Preferably, the process includes a post-processing step after the Suzuki coupling reaction, which is extraction and concentration. More preferably, the extraction involves adding water and stirring to obtain an aqueous phase, followed by stirring and further separation to obtain an organic phase. The concentration involves vacuum distillation of the organic phase.

[0046] Preferably, the extractant is one or more of toluene, ethyl acetate, methyl tert-butyl ether, and dichloromethane; more preferably, the extraction solvent is toluene. Those skilled in the art can determine the specific amounts of water and extractant added based on actual extraction operations, as long as the reaction product system can be separated into layers to facilitate phase separation. For example, specifically, the volume of water added during extraction is at least 5 times the volume of the compound of formula III, such as 6, 7, 8, 9, or 10 times, and the volume of the extractant added is at least 5 times the volume of the compound of formula III, such as 6, 7, 8, 9, or 10 times.

[0047] The fifth aspect of this application discloses an intermediate compound B, the structural formula of which is shown in Formula V:

[0048] .

[0049] The sixth aspect of this invention discloses a method for preparing intermediate compound B, which involves reacting a compound with tert-butyl diazoacetate under metal catalysis to form a three-membered ring, yielding the intermediate compound with the structure of Formula V. The reaction route is as follows:

[0050] .

[0051] Preferably, the molar ratio of compound IV to tert-butyl diazonyl acetate in the three-membered ring reaction is 1:(1~2), such as 1:1, 1:1.5, or 1:2. More preferably, it is 1:1.5. If the ratio is too small, too much tert-butyl diazonyl acetate will remain, leading to complicated separation and purification; if the ratio is too large, the reaction will be incomplete, resulting in a decrease in the yield of the target product.

[0052] Preferably, the reaction medium for the three-membered ring closure reaction is a fourth organic solvent, which is one or more of N,N-dimethylformamide, tetrahydrofuran, acetonitrile, and dichloromethane. More preferably, the organic solvent is dichloromethane.

[0053] Preferably, the three-membered ring closure reaction is carried out in the presence of a catalyst, which is one or more of rhodium trifluoroacetate, tetraethyl cyanoacetone hexafluorophosphate (abbreviated as [Cu(MeCN)4]PF6), and copper acetylacetonate (abbreviated as Cu(acac)2). More preferably, the catalyst is [Cu(MeCN)4]PF6.

[0054] More preferably, the molar ratio of the metal catalyst to the compound of formula IV is (0.001~0.05):1. The amount of catalyst used is the catalytically effective amount. If the amount of catalyst is too small, the reaction is very slow and the raw material conversion is insufficient; if the amount of catalyst is too large, the reaction cost will increase. Considering the reaction rate, reaction conversion rate and reaction cost, more preferably, the molar ratio is (0.03~0.05):1, such as 0.03:1, 0.04:1 or 0.05:1. More preferably, the molar ratio is 0.03:1.

[0055] Preferably, the reaction temperature for the three-membered ring closure reaction is 10–35°C, such as 10–15°C, 15–20°C, 20–25°C, 25–30°C, or 30–35°C. More preferably, the reaction temperature is 20–25°C. When the reaction temperature is above 35°C, side reactions increase and impurities in the system increase; when the reaction temperature is below 10°C, the reaction is very slow; when the reaction temperature is below 0°C, the reaction does not occur.

[0056] Preferably, the reaction time for the three-membered ring-closing reaction is 1 to 5 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours. More preferably, the reaction time is 1 hour.

[0057] Preferably, the reaction after the three-membered ring is closed further includes a post-processing step, which includes filtration, concentration, and recrystallization. More preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0058] More preferably, the recrystallization solvent used for recrystallization is one or more of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, n-hexane, and n-heptane. More preferably, the recrystallization solvent is a mixture of ethyl acetate and n-heptane.

[0059] The seventh aspect of the present invention discloses the use of a compound with the structure shown in Formula V for the preparation of lenakapavir intermediates.

[0060] The eighth aspect of this invention discloses a method for obtaining a compound with the structure described in Formula V and polyphosphoric acid (abbreviated as PPA) through a ring-closure reaction, wherein the reaction route is as follows:

[0061] .

[0062] Preferably, the mass ratio of PPA to compound V in the ring-closing reaction is (2~4):1, such as 2:1, 3:1, or 4:1. When the mass ratio of PPA as a dehydrating agent in the reaction is too large, excessive residual PPA will lead to complex separation and purification; when the ratio is too small, the reaction will be incomplete, resulting in a decreased yield of the target product. More preferably, the mass ratio is 2:1.

[0063] Preferably, the reaction medium for the ring-closing reaction is a fifth organic solvent, which is one or more of tetrahydrofuran, dichloromethane, or toluene. More preferably, the organic solvent is toluene.

[0064] Preferably, the reaction temperature for the ring-closure reaction is 90–110°C, such as 90–95°C, 95–100°C, 100–105°C, or 105–110°C. More preferably, the reaction temperature is 100–105°C. Below 90°C, the reaction is very slow; due to the boiling point limitation of the solvent, the maximum reaction temperature is 110°C. If a solvent with a higher boiling point is used, increasing the reaction temperature will increase side reactions and generate impurities.

[0065] Preferably, the reaction time for the ring-closing reaction is 10–16 h, such as 10 h, 12 h, 14 h, or 16 h. More preferably, the reaction time is 12 h.

[0066] Preferably, the reaction further includes a post-processing step, which includes extraction and concentration. More preferably, the extraction involves adding water and toluene, stirring, and then separating the phases to obtain an aqueous phase. Those skilled in the art can set specific amounts of water and toluene based on the actual operation of the extraction, as long as the phase separation objective of the extraction is achieved. For example, specifically, the volume of water added is at least 5 times the volume of the compound of formula V, such as 6, 7, 8, or 10 times; the volume of toluene added is at least 5 times the volume of the compound of formula V, such as 6, 7, 8, or 10 times. Preferably, the concentration involves vacuum distillation of the organic phase.

[0067] The ninth aspect of this invention discloses a method for fluorinating a compound with the structure described in Formula VI with a fluorinating reagent to obtain a final compound with the structure described in Formula VII, wherein the reaction route is as follows:

[0068] .

[0069] Preferably, the reaction medium for the fluorination reaction is a sixth organic solvent, which is one or more of methyl tert-butyl ether, tetrahydrofuran, or dichloromethane. More preferably, the organic solvent is dichloromethane.

[0070] Preferably, the fluorinating agent for the fluorination reaction is one or more of tetrabutylammonium fluoride (abbreviated as n-Bu4NF), sodium fluoride (abbreviated as NaF), potassium fluoride (abbreviated as KF), diethylaminosulfur trifluoride (abbreviated as DAST), or bis(2-methoxyethyl)aminosulfur trifluoride (abbreviated as BAST), and more preferably, the fluorinating agent is BAST.

[0071] Preferably, the molar ratio of compound VI to the fluorinating reagent in the fluorination reaction is 1:(2.5~4), such as 1:2.5, 1:3, 1:3.5 or 1:4. More preferably, it is 1:3. If the molar ratio is too small, too much fluorinating reagent will remain, increasing the reaction cost; if the molar ratio is too large, compound VI will remain, resulting in incomplete reaction.

[0072] Preferably, the reaction temperature for the fluorination reaction is -5 to 10°C, such as -5 to 0°C, 0 to 5°C, or 5 to 10°C. More preferably, the reaction temperature is 0 to 5°C. When the reaction temperature is too high (e.g., 20°C), side reactions increase and the reaction system becomes more impurity-rich; when the reaction temperature is below -5°C, the reaction is very slow.

[0073] Preferably, the fluorination reaction takes 72-80 hours, such as 72 hours, 74 hours, 76 hours, 78 hours, or 80 hours. More preferably, the reaction time is 72 hours. Since the reaction is a difluorination reaction, if the reaction time is less than 72 hours, the reaction will be incomplete, and the system will contain a monofluorinated intermediate. Therefore, the reaction time must be at least 72 hours, and extending the reaction time will not affect the reaction. Based on considerations of reaction efficiency and cost, the reaction time is limited to 72-80 hours.

[0074] Preferably, the fluorination reaction further includes a post-treatment step, which includes extraction and concentration. Preferably, the extraction involves adding a saturated sodium bicarbonate aqueous solution and dichloromethane, stirring, and then separating the layers to obtain an organic phase. Those skilled in the art can set specific amounts of saturated sodium bicarbonate aqueous solution and dichloromethane based on actual extraction operations, as long as the reaction product system can be separated into layers to facilitate phase separation. For example, specifically, the volume of sodium bicarbonate aqueous solution added during extraction is at least 10 times the volume of the compound of formula VI, such as 11, 12, or 13 times. More preferably, the volume of dichloromethane is at least 10 times the volume of the compound of formula VI. More preferably, the concentration involves vacuum distillation of the organic phase.

[0075] The tenth aspect of this invention discloses a method for obtaining a lenakapavir intermediate with the structural formula VIII by hydrolysis of a compound with the structure described in Formula VII under alkaline conditions, as follows:

[0076] .

[0077] Preferably, the reaction medium for the hydrolysis reaction is a seventh organic solvent, which is one or more of tetrahydrofuran (THF), methanol, or ethanol. More preferably, the organic solvent is THF.

[0078] Preferably, the hydrolysis reaction system contains an alkaline auxiliary agent, which is one or more of potassium hydroxide (KOH), sodium hydroxide (NaOH), or lithium hydroxide (LiOH). The alkaline auxiliary agent provides hydroxide ions in the hydrolysis reaction, promoting its progress. More preferably, the alkaline auxiliary agent is LiOH.

[0079] More preferably, the molar ratio of the basic auxiliary agent to the compound of formula VII is (2~3):1. For example, it can be 2:1, 2.5:1 or 3:1. If the molar ratio is too large, it will result in too much residual basic auxiliary agent, which will increase the amount of acidifying reagent added during post-processing and increase costs; if the molar ratio is too small, it will result in residual compound of formula III and incomplete reaction. More preferably, the molar ratio is 2:1.

[0080] Preferably, the hydrolysis reaction temperature is 0–25°C, such as 0–5°C, 5–10°C, 10–15°C, 15–20°C, or 20–25°C. When the reaction temperature is above 25°C, the reaction produces more impurities, making separation and purification difficult; when the reaction temperature is below 0°C, the reaction is very slow. More preferably, the reaction temperature is 0–5°C.

[0081] Preferably, the hydrolysis reaction takes 5 to 10 hours, such as 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours. More preferably, the reaction time is 5 hours.

[0082] Preferably, the hydrolysis reaction further includes a post-treatment step, which includes acidification, extraction, concentration, and recrystallization. Preferably, the acidification involves adding 6M hydrochloric acid dropwise to the reaction system to adjust the pH to 2-3, and obtaining an aqueous phase by separation. The extraction solvent is one or more of DCM, ethyl acetate, isopropyl acetate, and methyl tert-butyl ether; more preferably, the extraction solvent is isopropyl acetate. The concentration involves vacuum distillation of the organic phase.

[0083] Preferably, the recrystallization requires the use of a purification solvent, which is one or more of tetrahydrofuran, methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, n-hexane, and n-heptane. More preferably, the purification solvent is a mixture of isopropyl acetate and n-heptane.

[0084] The preparation method provided by this invention can obtain high-quality products without the need for silica gel column separation and purification, or cumbersome post-processing operations. This avoids complicated separation and purification steps, prevents waste of raw materials, reduces production costs, and is more suitable for industrial production. Attached Figure Description

[0085] Figure 1 This is a flowchart illustrating the preparation route of compounds with the structural formula of Formula II in the examples.

[0086] Figure 2 This is a flowchart illustrating the preparation route of compounds with the structural formula of Formula III in the examples.

[0087] Figure 3 This is a flowchart illustrating the preparation route of compounds with the structural formula of formula IV in the examples.

[0088] Figure 4 This is a flowchart illustrating the preparation route of compounds with the structural formula V in the examples.

[0089] Figure 5 This is a flowchart illustrating the preparation route of compounds with the structural formula of formula VI in the examples.

[0090] Figure 6 This is a flowchart illustrating the preparation route of compounds with the structural formula VII in the examples.

[0091] Figure 7 This is a flowchart illustrating the preparation route of compounds with the structural formula VIII as described in the examples.

[0092] Figure 8 This is a complete flowchart of the synthesis process.

[0093] Figure 9 The image shows the HPLC spectrum of the compound with the structural formula VIII prepared in the examples.

[0094] Figure 10 The chiral spectrum of the compound with the structural formula VIII prepared in the examples is shown. Detailed Implementation

[0095] The following specific examples illustrate the implementation of the present invention. Those skilled in the art can easily understand other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed based on different viewpoints and applications without departing from the spirit of the present invention.

[0096] Furthermore, it should be understood that the one or more method steps mentioned in this invention do not preclude the existence of other method steps before or after the combined steps, or the insertion of other method steps between these explicitly mentioned steps, unless otherwise stated. Moreover, unless otherwise stated, the numbering of each method step is merely a convenient tool for identifying each method step, and not intended to limit the order of the method steps or to limit the scope of the invention. Changes or adjustments to their relative relationships, without substantially altering the technical content, should also be considered within the scope of the invention.

[0097] The room temperature in this application is 25℃±5℃.

[0098] The HPLC analytical method in this application embodiment is as follows:

[0099] Instrument: Shimadzu LC-20A

[0100] Column: THERMO ACCLAIM C18 150*4.6*5um

[0101] Detection wavelength: 235nm

[0102] Mobile phases: Phase A: 0.1% aqueous phosphoric acid solution; Phase B: 90% aqueous acetonitrile solution.

[0103] Sample solution preparation: 1 mg / ml acetonitrile solvent

[0104] Flow rate: 1.0 mL / min

[0105] Column temperature: 35℃

[0106] Injection volume: 10 μL

[0107] Washing process

[0108] Time (min) Phase A (%) Phase B (%) 0.01 95 5 3.00 95 5 30.00 5 95 50.00 5 95 50.01 95 5 60.00 95 5

[0109] The chiral identification detection method for compound VIII in this application is illustrated in the embodiments.

[0110] Instrument: Shimadzu LC-20A

[0111] Column: Taisailu OJ 4.6*250*5um

[0112] Detection wavelength: 214nm

[0113] Mobile phase: 30% ethanol: n-hexane

[0114] Sample solution preparation: Dissolve in 1 mg / ml ethanol

[0115] Flow rate: 0.5 mL / min

[0116] Column temperature: 30℃

[0117] Injection volume: 5ul

[0118] Washing procedure: Isocratic washing for 30 minutes

[0119] Example 1

[0120] This embodiment is as follows: Figure 1 Synthetic route shown: Preparation of compounds with structures as shown in Formula II.

[0121] Acetonitrile (14 L, 10 vol), compound I (1.4 kg, 1.0 eq), and dibromohydantoin (1.76 kg, 0.6 eq) were added to the reaction vessel. The reaction was heated to 85 °C and carried out at this temperature for 16 hours. After cooling to room temperature, a saturated sodium sulfite aqueous solution (80 L) was slowly added to quench the reaction. The solution was then neutralized with potassium carbonate aqueous solution, and the pH was checked to be 9-10. Finally, the mixture was extracted twice with ethyl acetate (140 L). The combined organic layers were washed twice with saturated brine (70 L) and dried over anhydrous sodium sulfate. The solvent was removed by filtration and vacuum concentration to obtain 1.95 kg of the target product, with a yield of 88.17%.

[0122] The NMR and mass spectrometry data of the prepared compound of formula II are as follows: ¹H NMR (400 MHz, CDCl₃) 7.6 (s, ¹H), 4.00 (s, ¹H). MS: m / z = 216.05 (M+H). + .

[0123] Example 2

[0124] This embodiment is as follows: Figure 2 The synthetic route shown is for the preparation of compounds with structures as shown in Formula III.

[0125] Acetonitrile (36 L, 20 Vol), compound II (1.8 kg, 1.0 eq), and potassium carbonate (1.39 kg, 2.0 eq) were added to the reaction vessel. The mixture was heated to 55°C and stirred for 30 minutes, then cooled to room temperature. Ethyl bromoacetate (1.54 kg, 1.1 eq) was added to the reaction vessel. After the addition was complete, the mixture was heated to 85°C and stirred for 6 hours. The reaction mixture was cooled to 50°C and concentrated under reduced pressure until no fraction remained. Dichloromethane (20 L) was added to the residue, and the mixture was washed twice with water (10 L). The liquid and liquid phases were separated and combined. The product was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2.1 kg of product, with a yield of 83.3%.

[0126] The NMR and mass spectrometry data of the prepared compound of formula III are as follows: ¹H NMR (400 MHz, CDCl₃) 7.49 (s, ¹H), 5.83 (s, 2H), 4.24 (m, 2H), 1.29 (t, 3H). MS: m / z = 302.07 (M+H) + .

[0127] Example 3

[0128] This embodiment is as follows: Figure 3 The synthetic route shown is for the preparation of compounds with structures as shown in Formula IV.

[0129] Toluene (12 L, 10 Vol) and Compound III (1.2 kg, 1.0 eq) were added to the reactor. Under argon protection, the mixture was heated to 105°C and stirred under reflux for 3 hours to remove oxygen. The reaction mixture was then cooled to room temperature under argon protection. Vinyl borate pinacol ester (767.7 g, 1.2 eq), potassium acetate (1.17 kg, 3.0 eq), and Pd(dppf)Cl2 (73 g, 0.025 eq) were added to the reactor. After the addition was complete, the reactor was purged with argon for 1 hour. The reaction mixture was then heated to 105°C and stirred for 22 hours.

[0130] After the raw material conversion was completed and the reaction was cooled to room temperature, water (6 L, 5 Vol) was added to the reactor, and the mixture was stirred and separated. The aqueous phase was extracted twice with toluene (6 L, 5 Vol). The organic phases were combined and washed twice with saturated brine (6 L, 5 Vol). The organic phase obtained after separation was dried over anhydrous sodium sulfate, concentrated to remove toluene, and the crude product was slurried in n-heptane (12 L, 10 Vol) at a controlled temperature of 0-5°C. After filtration, 750 g of compound IV was obtained, with a yield of 75.8%.

[0131] The NMR and mass spectrometry data of the prepared compound of formula IV are as follows: ¹H NMR (400 MHz, CDCl₃): 8.29 (s, ¹H), 6.75 (t, ¹H), 5.83 (s, 2H), 5.56 (d, 2H), 4.24 (m, 2H), 1.29 (t, 3H). MS: m / z = 249.32 (M+H) + .

[0132] Example 4

[0133] This embodiment is as follows: Figure 4 The synthetic route shown is for the preparation of compounds with structures as shown in Formula V.

[0134] [Cu(MeCN)4]PF6 (31.5 g, 0.03 eq) was dissolved in DCM (3.5 L, 5 vol) at room temperature under nitrogen protection. After stirring the solution for 5 minutes, intermediate IV compound (700 g, 1.0 eq) was added. The mixture was stirred at 25 °C for 5 minutes, and then a solution of dichloromethane (3.5 L, 5 vol) containing ethyl diazonium acetate (601.3 g, 1.5 eq) was added over a 5-hour period using a syringe pump. After stirring for one hour, the mixture was washed successively with saturated sodium bicarbonate aqueous solution (1.4 L, 2 vol) and water (1.4 L, 2 vol). The organic phase was dried over anhydrous Na2SO4 and all volatiles were removed under vacuum. The crude product was recrystallized and added to ethyl acetate (EA) (1.4 L, 2 Vol), followed by the addition of n-heptane (3.5 L, 5 Vol). After stirring for 2 h, the mixture was filtered and dried to obtain 838 g of compound V, with a yield of 82%.

[0135] The NMR and mass spectrometry data of the prepared compound of formula V are as follows: ¹H NMR (400 MHz, CDCl₃): 8.29 (s, ¹H), 5.83 (s, 2H), 4.24 (m, 2H), 2.21 (m, ¹H), 1.57 (d, ¹H), 1.43 (s, 9H), 1.29 (t, 3H), 0.95 (m, 2H). MS: m / z = 363.45 (M+H) + .

[0136] Example 5

[0137] This embodiment is as follows: Figure 5 The synthetic route shown is for the preparation of compounds with structures as shown in Formula VI.

[0138] Toluene (15 L, 10 Vol) and PPA (3.0 kg) were added to a mechanically stirred 50 L reactor, and the reaction was heated to 90 °C. The temperature was maintained at 90 ± 5 °C, and compound V (1.5 kg, 6 mol) was dissolved in toluene (7.5 L, 5 Vol). This solution was then slowly added dropwise to the toluene solution of PPA in the reaction mixture. After the addition was complete, the reaction mixture was heated to 105 °C and refluxed for 12 hours. Once the reactants had reacted completely, the reaction was cooled to 25 ± 5 °C, and water (7.5 L, 5 Vol) was slowly added to the reactor. After the addition was complete, the mixture was allowed to stand and separated. The aqueous phase was extracted once with toluene (7.5 V, 5 Vol). The combined organic phases were washed twice with saturated brine (7.5 L, 5 Vol), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 1063 g of the intermediate product, compound VI, with a yield of 89.1%.

[0139] The NMR and mass spectrometry data of the prepared compound of formula VI are as follows: ¹H NMR (400 MHz, CDCl₃): 5.83 (s, 2H), 4.24 (m, 2H), 2.21 (m, 2H), 1.29 (t, 3H), 0.95 (m, 2H). MS: m / z = 289.33 (M+H) + .

[0140] Example 6

[0141] This embodiment is as follows: Figure 6 The synthetic route shown is for the preparation of compounds with structures as shown in Formula VII.

[0142] Under nitrogen protection, dichloromethane (16 L, 20 Vol) and intermediate compound VI (800 g, 1.0 eq) were added to a reaction vessel. The temperature was controlled at 0–5°C, and BAST (1842 g, 3.00 eq) was slowly added dropwise under nitrogen protection. The mixture was stirred at room temperature for 72 hours. The reaction was quenched at 0°C by adding sodium bicarbonate solution (8 L, 10 Vol). The resulting mixture was extracted twice with dichloromethane (2 L). The combined organic layers were washed twice with sodium bicarbonate solution (5 wt%, 5 L) and then with saturated brine (5 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 740 g of compound VII, in 86% yield.

[0143] The NMR and mass spectrometry data of the prepared compound of formula VII are as follows: ¹H NMR (400 MHz, CDCl₃): 5.83 (s, 2H), 4.24 (m, 2H), 2.21 (m, 2H), 1.29 (t, 3H), 0.95 (m, 2H). MS: m / z = 311.33 (M+H) + .

[0144] Example 7

[0145] This embodiment is as follows: Figure 7 The synthetic route shown is for the preparation of compounds with structures as shown in Formula VIII.

[0146] Compound VII (700 g, 1.0 eq) and THF (7 L, 10 Vol) were added to a mechanically stirred 20 L reactor. The mixture was cooled to 0–5 °C, and 10% lithium hydroxide solution (108.3 g, 2 eq) was added dropwise. After the addition was complete, the mixture was reacted at room temperature for 5 h. The pH was adjusted to 2–3 by adding 6 M hydrochloric acid. The mixture was separated into liquid and liquid phases. The aqueous phase was extracted again with isopropyl acetate (3.5 L, 5 Vol). The organic phases were combined and washed with saturated brine (3.5 L × 2). The organic phases were dried with anhydrous sodium sulfate and concentrated under vacuum to obtain a crude product. The crude product was dissolved in isopropyl acetate (1.4 L, 2 Vol), and n-heptane (3.5 L, 5 Vol) was added dropwise. The mixture was filtered and dried to obtain 541 g of compound VIII, with a yield of 85%. The purity was 99.82%. No chiral impurities were found.

[0147] The NMR and mass spectrometry data of the prepared compound of formula VIII are as follows: ¹H NMR (400 MHz, CDCl₃) 5.83 (s, 2H), 2.21 (m, 2H), 0.95 (m, 2H). MS: m / z = 283.22 (M+H). + .

[0148] Figure 9 The image shows the HPLC spectrum of the compound with the structural formula VIII prepared in the examples.

[0149] Figure 10 Time (min) Phase A (%) Phase B (%) The chiral spectrum of the compound with the structural formula VIII prepared in the examples is shown.

[0150] The above embodiments are merely illustrative of the principles and effects of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in the present invention should still be covered by the claims of the present invention.

Claims

1. An intermediate compound A, characterized in that, The structural formula of intermediate compound A is shown in Formula IV: 。 2. A method for preparing intermediate compound A as described in claim 1, characterized in that, The compound with structural formula III was subjected to a Suzuki coupling reaction with vinylboronic acid pinacol ester under metal catalysis to obtain the intermediate compound with structural formula IV. The reaction route is as follows: 。 3. The synthesis method according to claim 2, characterized in that, In the Suzuki coupling reaction, the molar ratio of compound III to pinacol vinylboronic acid is 1:(1.2~1.5). And / or, the reaction system of the Suzuki coupling reaction further includes a metal catalyst, wherein the metal catalyst is one or more selected from Pd(dba)2, Pd(PPh3)4, Pd(t-Bu3P)2, Pd(dppf)Cl2 or Pd(dppf)Cl2 dichloromethane complex; the molar ratio of the metal catalyst to the compound of formula III is (0.001~0.1):1; And / or, the reaction system of the Suzuki coupling reaction also includes a basic auxiliary agent, which is one or more of sodium bicarbonate, potassium carbonate, sodium carbonate, sodium acetate or potassium acetate; the molar ratio of the basic auxiliary agent to the compound of formula III is (2~4):1; And / or, the reaction system of the Suzuki coupling reaction further includes a third organic solvent, which is selected from one or more of toluene, dioxane, N,N-dimethylformamide, and tetrahydrofuran; And / or, the reaction temperature of the Suzuki coupling reaction is 100–110 °C; And / or, after the Suzuki coupling reaction is completed, a post-processing step is included, which is extraction and concentration.

4. The synthesis method according to claim 2, characterized in that, The compound with the structure shown in Formula III is prepared by a substitution reaction of the compound with the structure shown in Formula II and ethyl bromoacetate, and the reaction route is as follows: 。 5. The synthesis method according to claim 4, characterized in that, In the substitution reaction, the molar ratio of compound II to ethyl bromoacetate is 1:(1–1.5). And / or, the reaction system of the substitution reaction also includes a basic auxiliary agent, which is one or more of potassium phosphate, potassium carbonate, sodium carbonate or cesium carbonate; the molar ratio of the basic auxiliary agent to the compound of formula II is (1~4):1; And / or, the reaction system of the substitution reaction also includes a second organic solvent, which is one or more selected from acetonitrile, DCM, THF, and EtOH; And / or, the reaction temperature for the substitution reaction is 65–85 °C; And / or, after the substitution reaction is completed, a post-processing step is also included, which includes washing and concentration.

6. The synthesis method according to claim 4, characterized in that, The compound with the structure shown in Formula II is prepared by a bromination reaction of the compound with the structure shown in Formula I and a brominating reagent, as follows: 。 7. The synthesis method according to claim 6, characterized in that, The brominating reagent in the reaction system of the bromination reaction is one or more of NBS, Br2 or DBDMH; the molar ratio of the brominating reagent to the compound of formula I is (0.5~1):1; And / or, the reaction system of the bromination reaction further includes a first organic solvent, which is one or more selected from N,N-dimethylformamide, toluene, chloroform, dichloromethane, dichloroethane, carbon tetrachloride and acetonitrile; And / or, the reaction temperature for bromination is 65–85 °C; And / or, after the bromination reaction is completed, a post-processing step is also included, which includes quenching, extraction and concentration.

8. An intermediate compound B, characterized in that, The structural formula of the intermediate compound B is shown in Formula V: 。 9. A method for preparing intermediate compound B as described in claim 8, characterized in that, The compound with the structural formula of Formula IV as described in claim 1 is reacted with tert-butyl diazoacetate via a three-membered ring-closing reaction to obtain the intermediate compound with the structural formula of Formula V. The reaction route is as follows: 。 10. The synthesis method according to claim 9, characterized in that, In the three-membered ring reaction, the molar ratio of compound IV to tert-butyl diazonyl acetate is 1:(1~2). And / or, the reaction system for the three-membered ring reaction further includes a catalyst, wherein the catalyst is one or more of rhodium trifluoroacetate, [Cu(MeCN)4]PF6 or Cu(acac)2; the molar ratio of the metal catalyst to the compound of formula IV is (0.001~0.05):1; And / or, the reaction system for the three-membered ring reaction further includes a fourth organic solvent, wherein the fourth organic solvent is one or more selected from N,N-dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane; And / or, the reaction temperature for the three-membered ring closure reaction is 10–35 °C; And / or, after the three-membered ring reaction is completed, a post-processing step is also included, which is filtration, concentration and recrystallization.

11. Use of a compound of formula V as described in claim 8 as a substrate for the preparation of a lenakapavir intermediate compound of formula VIII.

12. A method for synthesizing the compound of formula VIII, characterized in that, 1) A compound with the structure described in Formula V was reacted with PPA via a ring-closure reaction to obtain a compound with the structure described in Formula VI. The reaction route is as follows: ； 2) Fluorination is performed using a compound with the structure described in Formula VI and a fluorinating reagent to obtain a compound with the structure described in Formula VII. The reaction route is as follows: ； 3) The compound with the structure described in Formula VII is subjected to a hydrolysis reaction to obtain the compound with the structure described in Formula VIII. The reaction route is as follows: 。 13. The synthesis method according to claim 12, characterized in that, In step 1), the mass ratio of PPA to compound V in the ring-closing reaction is (2~4):1; And / or, the reaction system of step 1) cyclization reaction further includes a fifth organic solvent, which is one or more selected from tetrahydrofuran, dichloromethane or toluene; And / or, the reaction temperature for step 1) the ring-closing reaction is 90–110 °C; And / or, after the ring-closing reaction in step 1), a post-processing step is included, which is extraction and concentration; And / or, in step 2), the fluorinating agent for the fluorination reaction is one or more of n-Bu4NF, NaF, KF, DAST, or BAST; And / or, in step 2), the molar ratio of compound VI to the fluorinated reagent in the fluorination reaction is 1:(2.5~4). And / or, the reaction system of the fluorination reaction in step 2) further includes a sixth organic solvent, which is one or more selected from methyl tert-butyl ether, tetrahydrofuran or dichloromethane; And / or, in step 2), the reaction temperature for the fluorination reaction is -5 to 10°C; And / or, after the fluorination reaction is completed in step 2), a post-processing step is also included, which is extraction and concentration; And / or, the reaction system of the hydrolysis reaction in step 3) further includes a seventh organic solvent, which is one or more selected from THF, methanol or ethanol; And / or, the reaction system of the hydrolysis reaction in step 3) contains an alkaline auxiliary agent, wherein the alkaline auxiliary agent is one or more of KOH, NaOH or LiOH; the molar ratio of the alkaline auxiliary agent to the compound of formula VII is (2~3):1; And / or, the reaction temperature for step 3) of the hydrolysis reaction is 0–25°C; And / or, after the hydrolysis reaction in step 3) is completed, a post-treatment step is also included, which is acidification, extraction, concentration and recrystallization.

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