An intermediate of gipodacene and a preparation method thereof

Abstract

The application provides an intermediate compound of gipodacine and a preparation method thereof, and a structural formula of the intermediate compound A is shown as formula II. The intermediate and the preparation method thereof can obtain high-quality gipodacine and intermediate thereof, the intermediate product does not need to be separated and purified by using a silica gel column, and does not need complicated post-treatment operation, avoids complicated separation and purification steps, avoids waste of raw materials, reduces production cost, and is more suitable for industrial production.

Description

Technical Field

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

[0002] Gepotidacin is a novel, orally active triazaacenaphthene-based bacterial type II topoisomerase inhibitor, first approved by the U.S. Food and Drug Administration (FDA) in 2025. It exerts its bactericidal effect by inhibiting bacterial DNA gyrase (encoded by the gyrA and gyrB genes) and topoisomerase IV (encoded by the parC and parE genes), thus blocking bacterial DNA replication. Its target is similar to that of fluoroquinolone antibiotics (such as ciprofloxacin), but they differ in structure and pharmacology. By inhibiting two different bacterial enzymes, gepotidacin is expected to have a low likelihood of developing resistance.

[0003] The structural formula of Gibbada Star is as follows:

[0004] The CAS number is 1075236-89-3.

[0005] In the existing technology, there is a lack of a new synthetic route with simple post-processing operations, which cannot meet the needs of large-scale industrial production. Summary of the Invention

[0006] In view of the shortcomings of the prior art described above, the purpose of this invention is to provide an intermediate of gipodacin and a method for preparing the same, thereby providing a novel intermediate of gipodacin and a method for preparing the same, which has a higher yield and simpler post-processing steps, making it more suitable for large-scale industrial production.

[0007] To achieve the above and other related objectives, the present invention is implemented by including the following technical solutions.

[0008] This invention first claims protection for an intermediate compound A, the structural formula of which is shown in Formula II:

[0009] .

[0010] This invention also discloses a method for preparing intermediate compound A, which involves reacting a compound with L-serine methyl ester hydrochloride via a substitution reaction to obtain an intermediate compound with the structure of Formula II. The reaction route is as follows:

[0011] .

[0012] Among them, the compound with the structural formula as described in Formula I is 2-chloro-6-methoxy-3-nitropyridine.

[0013] Preferably, the above substitution reaction also employs a reaction medium, which is an organic solvent. Considering factors such as solvent cost, availability, and solubility, more preferably, the organic solvent is one or both of DMF and ethanol. More preferably, the organic solvent is ethanol.

[0014] Generally, the ratio of reactants to reactants in this application is adjusted to ensure that the reaction proceeds as fully as possible.

[0015] Preferably, the molar ratio of the compound with the structural formula as described in Formula I to L-serine methyl ester hydrochloride is 1:(0.9~1.2), such as 1:1, 1:1.05, 0.9:1, etc.

[0016] Preferably, the substitution reaction is carried out under alkaline conditions to neutralize the acid produced in the reaction, promote the forward reaction, and thus increase the yield. More preferably, the base is selected from one or more of potassium carbonate, sodium acetate, or triethylamine. More preferably, the base is triethylamine.

[0017] In the above substitution reaction, if the reaction temperature is below 50°C, the reaction is very slow or even fails; reflux occurs at 78°C. Preferably, the reaction temperature in the above substitution reaction is 60–78°C, such as 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, or 78°C. More preferably, the reaction temperature is 70–78°C.

[0018] Preferably, the above substitution reaction further includes a post-treatment step, which includes extraction and concentration. More preferably, the extraction reagents used are water and ethyl acetate. For example, after the reaction, water and ethyl acetate are added to the reaction system and stirred to obtain an organic phase by separation. The specific amounts of water and ethyl acetate can be adjusted according to the actual reaction conditions to facilitate phase separation. More preferably, the volume of water is at least twice the volume of the compound of Formula I, such as three, four, or five times. More preferably, the volume of ethyl acetate is at least four times the volume of the compound of Formula I. Preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0019] This application also discloses an intermediate compound B, the structural formula of which is shown in Formula III:

[0020] .

[0021] This invention also discloses a method for preparing intermediate compound B, which involves a cyclization reaction between a compound with the structure described in Formula II and methanesulfonic acid anhydride to obtain the intermediate compound with the structure described in Formula III. The reaction route is as follows:

[0022] .

[0023] Preferably, the above-described ring-closing reaction uses a reaction medium, which is an organic solvent. Generally, the organic solvent is chosen considering factors such as cost, ease of operation, and solubility. More preferably, the organic solvent is selected from one or more of acetonitrile and dichloromethane (DCM). More preferably, the organic solvent is DCM.

[0024] Preferably, the molar ratio of the compound of Formula II to methanesulfonic acid anhydride is 1:1 to 2, such as 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, etc.

[0025] Preferably, the ring-closure reaction is carried out under alkaline conditions to act as an acid neutralizer, neutralizing the acid produced during the reaction and promoting the forward reaction to increase the yield. More preferably, the base is selected from one or more of potassium carbonate, sodium acetate, and triethylamine. More preferably, the base is triethylamine.

[0026] In the ring-closing reaction, if the reaction temperature is too low, such as below 20°C, the reaction will be very slow or even fail to occur. 40°C is the reflux temperature. Preferably, in the ring-closing reaction, the reaction temperature is 30–40°C, such as 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, or 40°C. More preferably, the reaction temperature is 35–40°C.

[0027] Preferably, the reaction further includes a post-processing step after the ring-closing reaction, which includes extraction and concentration. The extraction reagent is water, and water and dichloromethane can form a two-phase system. The amount of water added can be controlled according to the actual reaction's phase separation requirements. More preferably, the volume of water is at least twice the volume of the compound of Formula I, such as three, four, or five times. Preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0028] This application also discloses an intermediate compound C, the structural formula of which is shown in Formula IV:

[0029] .

[0030] This invention also discloses a method for preparing intermediate compound C, which involves reacting a compound with chloroacetyl chloride via a substitution reaction to obtain the intermediate compound with the structural formula of Formula III. The reaction route is as follows:

[0031] .

[0032] Preferably, the reaction medium in the above reaction is an organic solvent. Considering cost, availability, solubility, and the difficulty of post-processing, more preferably, the organic solvent is selected from one or more of toluene and THF. More preferably, the organic solvent is THF.

[0033] Preferably, the molar ratio of the compound with the structural formula as described in Formula III to chloroacetyl chloride is 1:1 to 1.5, such as 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0034] Preferably, the molar ratio of the compound with the structural formula as described in Formula III to the sodium hydrogen is 1:1 to 1.5, such as 1:1.1, 1:1.2, 1:1.3, 1:1.4, or 1:1.5.

[0035] Preferably, the reaction is carried out under alkaline conditions. More preferably, the base is selected from one or more of n-butyllithium, potassium tert-butoxide, and sodium hydrogen. Considering the amount of impurities generated by side reactions and the yield, sodium hydrogen is more preferably the base. Compared with using sodium hydrogen, using n-butyllithium and potassium tert-butoxide will generate more impurities, which will affect the yield to some extent. That is, the yield is not as high as that of using sodium hydrogen, and the post-processing is also more complicated than that of using sodium hydrogen.

[0036] The substitution reaction temperature must not be too high to ensure the safety and stability of the reaction. Preferably, the reaction temperature in the above substitution reaction is 0–50°C. For example, it can be 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C. More preferably, the reaction temperature is 20–25°C.

[0037] Preferably, the reaction further includes a post-processing step, which includes extraction and concentration. More preferably, the extraction reagents used are water and ethyl acetate, such as adding water and ethyl acetate to the reaction system, stirring, and then separating the layers to obtain an aqueous phase. The specific amounts of water and ethyl acetate added can be adjusted according to the actual reaction system, as long as it facilitates layer separation. More preferably, the volume of water is at least twice the volume of the compound of Formula I, such as three, four, or five times. More preferably, the volume of ethyl acetate is at least four times the volume of the compound of Formula I. Preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0038] This application also discloses an intermediate compound D, the structural formula of which is shown in Formula V:

[0039] .

[0040] This invention also discloses a method for preparing intermediate compound D, which involves reacting a compound with hydrogen gas to form an intermediate compound with the structure described in Formula IV, thereby obtaining the intermediate compound with the structure described in Formula V. The reaction route is as follows:

[0041] .

[0042] Preferably, the reaction medium in the above-described cyclization reaction is an organic solvent. More preferably, considering solubility, availability, cost, etc., the organic solvent is selected from one or more of methanol and THF. More preferably, the organic solvent is methanol.

[0043] Preferably, the cyclization reaction is carried out under a catalyst. More preferably, the catalyst is palladium on carbon or Raney nickel. More preferably, the catalyst is palladium on carbon. The amount of catalyst used is the catalytically effective amount (e.g., 0.001wt~20wt% of the substrate, such as 0.001wt%, 0.01wt%, 0.1wt%, 0.5wt%, 1wt%, 5wt%, 10wt%, etc.). Compared with using palladium on carbon, using Raney nickel results in more impurities in the reaction product, a relatively lower yield, and more complicated post-processing.

[0044] Preferably, the above-mentioned cyclization reaction can be carried out at room temperature. Generally, it can also be carried out at a slightly fluctuating room temperature. Considering cost, reaction occurrence, and by-products, the reaction temperature can be 20–40°C, such as 20°C, 22°C, 25°C, 27°C, 30°C, 32°C, 35°C, 37°C, or 40°C. More preferably, the reaction temperature is 20–25°C.

[0045] Preferably, the cyclization reaction is carried out in a reaction vessel, such as a hydrogenation vessel, to provide a hydrogen reaction environment. The pressure in the reaction vessel during the cyclization reaction is 0.2~0.8 MPa, such as 0.3 MPa, 0.4 MPa, 0.5 MPa, 0.6 MPa, 0.7 MPa, or 0.8 MPa.

[0046] Preferably, the cyclization reaction further includes a post-processing step, which includes filtration and concentration. Preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0047] This application also discloses an intermediate compound E, the structural formula of which is shown in Formula VI:

[0048] .

[0049] This invention also discloses a method for preparing intermediate compound E, which involves a reduction reaction of a compound with the structure described in Formula V with sodium borohydride or potassium borohydride to obtain an intermediate compound with the structure described in Formula VI. The reaction route is as follows:

[0050] .

[0051] Preferably, the reaction medium in the above reduction reaction is an organic solvent. More preferably, considering cost, availability, and solubility, the organic solvent is one or both of THF and methanol. More preferably, the organic solvent is methanol.

[0052] Preferably, the molar ratio of the compound with the structural formula as described in Formula V to sodium borohydride or potassium borohydride is 1:1.9 to 2.5, such as 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, or 1:2.5.

[0053] The reduction reaction can be carried out at room temperature. Considering the reaction byproducts, appropriate temperature variations within the room temperature range are generally permissible. Preferably, the reduction reaction temperature is 10–50°C, such as 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, or 50°C. More preferably, the reaction temperature is 20–25°C.

[0054] Preferably, the reduction reaction further includes a post-processing step, which includes extraction and concentration. More preferably, the extraction reagent includes water and ethyl acetate. Specifically, water and ethyl acetate are added to the reaction system, stirred, and then separated into layers to obtain an aqueous phase. The amounts of water and ethyl acetate added can be set according to the actual phase separation situation, as long as it can easily achieve phase separation. More preferably, the volume of water is at least twice the volume of the compound of Formula I, such as three times, four times, five times, etc. More preferably, the volume of ethyl acetate is at least four times the volume of the compound of Formula I. Preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0055] The present invention further discloses the entire reaction route for synthesizing gipotassium using an intermediate compound with the structural formula as described in Formula VI. Further elaboration follows.

[0056] This application also discloses intermediate compound F, the structural formula of which is shown in Formula VII:

[0057] .

[0058] This invention also discloses a method for preparing intermediate F, which involves reacting a compound with the structure described in Formula VI with manganese dioxide to obtain the final product with the structure described in Formula VII. The reaction route is as follows:

[0059] .

[0060] Preferably, the reaction medium in the above reaction is an organic solvent. More preferably, the organic solvent is one or both of methyl tert-butyl ether (MTBE) and DCM. More preferably, the organic solvent is DCM.

[0061] Preferably, the reaction further includes a post-processing step, which includes concentrated filtration and concentration. More preferably, the reaction solution is extracted and concentrated to dryness.

[0062] This application also discloses intermediate compound G, the structural formula of which is shown in Formula VIII:

[0063] .

[0064] This invention also discloses a method for preparing intermediate G, which involves reacting a compound with the structure described in Formula VII with methanesulfonyl chloride to obtain the final product with the structure described in Formula VIII. The reaction route is as follows:

[0065] .

[0066] Preferably, the reaction medium in the above reaction is an organic solvent. More preferably, the organic solvent is one or both of tetrahydrofuran (THF) and DCM. More preferably, the organic solvent is DCM.

[0067] Preferably, the reaction is carried out under alkaline conditions. More preferably, the base is potassium carbonate or triethylamine. More preferably, the base is triethylamine.

[0068] Preferably, the reaction temperature is 0–10°C. More preferably, the reaction temperature is 0–5°C.

[0069] Preferably, the reaction further includes a post-processing step, which includes extraction and concentration. More preferably, water is added and stirred to obtain an aqueous phase. More preferably, the volume of water is at least twice the volume of the compound of Formula I, such as three, four, or five times. Preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0070] This application also discloses intermediate compound H, the structural formula of which is shown in Formula IX:

[0071] .

[0072] This invention also discloses a method for preparing intermediate H, which involves reacting a compound with the structure described in Formula VIII with N-Boc-piperazine to obtain the final product with the structure described in Formula IX. The reaction route is as follows:

[0073] .

[0074] Preferably, the reaction medium in the above reaction is an organic solvent. More preferably, the organic solvent is one or both of THF and DCM. More preferably, the organic solvent is DCM.

[0075] Preferably, the reaction is carried out under alkaline conditions. More preferably, the base is potassium carbonate or triethylamine. More preferably, the base is triethylamine.

[0076] Preferably, the reaction temperature is 20–40°C. More preferably, the reaction temperature is 35–40°C.

[0077] Preferably, the reaction further includes a post-processing step, which includes extraction and concentration. More preferably, water is added and stirred to obtain an aqueous phase. More preferably, the volume of water is at least twice the volume of the compound of Formula I, such as three, four, or five times. Preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0078] This application also discloses intermediate compound I, the structural formula of which is shown in Formula X:

[0079] .

[0080] This invention also discloses a method for preparing intermediate I, which involves reacting a compound with the structure described in Formula IX with trifluoroacetic acid to obtain the final product with the structure described in Formula X. The reaction route is as follows:

[0081] .

[0082] Preferably, the reaction medium in the above reaction is an organic solvent. More preferably, the organic solvent is one or both of THF and DCM. More preferably, the organic solvent is DCM.

[0083] Preferably, the reaction is carried out under acidic conditions. More preferably, hydrochloric acid or trifluoroacetic acid is used. Even more preferably, the acid is trifluoroacetic acid.

[0084] Preferably, the reaction temperature is 20–40°C. More preferably, the reaction temperature is 20–25°C.

[0085] Preferably, the reaction further includes a post-processing step, which includes extraction and concentration. More preferably, an organic phase is obtained by stirring with sodium carbonate solution to obtain the organic phase. More preferably, the volume of the sodium carbonate solution is at least twice the volume of the compound of Formula I, such as three times, four times, five times, etc. Preferably, the concentration is achieved by vacuum distillation of the organic phase.

[0086] This application also discloses a final product compound J, the structural formula of which is shown in Formula XI:

[0087] .

[0088] This invention also discloses a method for preparing the final product J, which involves reacting a compound with the structure described in Formula X with 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carboxaldehyde to obtain the final product with the structure described in Formula XI. The reaction route is as follows:

[0089] .

[0090] Preferably, the reaction medium in the above reaction is an organic solvent. More preferably, the organic solvent is one or both of THF and ethanol. More preferably, the organic solvent is ethanol.

[0091] Preferably, the reducing agent is sodium borohydride or sodium triacetoxyborohydride. More preferably, the reducing agent is sodium triacetoxyborohydride.

[0092] Preferably, the reaction temperature is 20–40°C. More preferably, the reaction temperature is 20–25°C.

[0093] Preferably, the reaction further includes a post-processing step, which includes extraction, concentration, slurrying, and filtration. More preferably, water and ethyl acetate are added and stirred to obtain an aqueous phase by separation. More preferably, the volume of water is at least twice the volume of the compound of formula I, such as three, four, or five times. More preferably, the volume of ethyl acetate is at least four times the volume of the compound of formula I. Preferably, the concentration is carried out by vacuum distillation of the organic phase. More preferably, a mixture of ethyl acetate and n-heptane is added and slurryed. More preferably, the volume of ethyl acetate is one time the volume of the compound of formula X. More preferably, the volume of n-heptane is five times the volume of the compound of formula X. More preferably, the final product is filtered.

[0094] As described above, the complete invention title has the following beneficial effects:

[0095] The intermediate and its preparation method provided by this invention can obtain high-quality products such as gipotacin and its intermediates. Moreover, the intermediate products do not require silica gel column separation and purification, nor do they require cumbersome post-processing operations. This avoids complicated separation and purification steps, avoids waste of raw materials, reduces production costs, and is more suitable for industrial production. Attached Figure Description

[0096] Figure 1 This is a flowchart illustrating the preparation route of intermediate compound II in the examples.

[0097] Figure 2This is a flowchart illustrating the preparation route of compounds with the structural formula of Formula III in the examples.

[0098] Figure 3 This is a route diagram for the preparation of compounds with the structural formula shown in Formula IV.

[0099] Figure 4 This is a flowchart illustrating the preparation route of intermediate compound V in the examples.

[0100] Figure 5 This is a flowchart illustrating the preparation route of intermediate compound VI in the examples.

[0101] Figure 6 This is a flowchart illustrating the preparation route of the intermediate with the structural formula VII in the embodiments.

[0102] Figure 7 This is a flowchart illustrating the preparation route of the intermediate with the structural formula VIII in the embodiments.

[0103] Figure 8 This is a flowchart illustrating the preparation route of the intermediate with the structural formula XI in the embodiments.

[0104] Figure 9 This is a flowchart illustrating the preparation route of the intermediate with the structural formula X in the embodiments.

[0105] Figure 10 This is a flowchart illustrating the preparation route of the final product with the structural formula XI in the embodiments.

[0106] Figure 11 This is a specific synthetic route diagram for the overall synthesis of Gipoda star in the embodiments of this application. Detailed Implementation

[0107] 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.

[0108] It should be noted that the process equipment or apparatus not specifically mentioned in the following embodiments are all conventional equipment or apparatus in the art.

[0109] Furthermore, it should be understood that the existence of other method steps before or after the combined steps, or the insertion of other method steps between these explicitly mentioned steps, does 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. It should also be understood that the combined connection relationship between one or more devices / apparatus mentioned in this invention does not preclude the existence of other devices / apparatus before or after the combined devices / apparatus, or the insertion of other devices / apparatus between these explicitly mentioned devices / apparatus, 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 for limiting the order of the method steps or limiting 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.

[0110] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in the present invention, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description of this invention, any prior art methods, apparatus, and materials similar to or equivalent to those described, apparatus, and materials in the embodiments of this invention may be used to implement the present invention.

[0111] The following compounds and intermediates were characterized by nuclear magnetic resonance (NMR). The starting materials and reagents used in the preparation of these compounds were available from suppliers or prepared by methods known to those skilled in the art. The following general synthetic routes are merely illustrative of methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic routes are possible and inspired by those skilled in the art who have referred to this disclosure.

[0112] The term "contact" as used herein should be interpreted broadly, encompassing any method that enables at least two reactants to undergo a chemical reaction, such as mixing two reactants under appropriate conditions. If necessary, reactants requiring contact can be mixed under stirring; therefore, the type of stirring is not particularly limited, such as mechanical stirring, i.e., stirring under mechanical force.

[0113] In an exemplary embodiment of this application, the final product adopts as follows Figure 1 The route synthesis shown is illustrated in the following steps.

[0114] Example 1

[0115] Preparation of intermediate compound II.

[0116] Compound I (5 kg, 26.5 mol), ethanol (20 L), L-serine methyl ester hydrochloride (4.12 kg, 26.5 mol), and triethylamine (5.36 kg, 53 mol) were added to a 100 L mechanically stirred reactor and reacted at 70–78 °C for 20 h.

[0117] Post-processing: The reaction solution was cooled to room temperature, water (40L) was added, followed by ethyl acetate (20L). After stirring for 10 minutes, the organic phase was separated and concentrated under vacuum to obtain 6.1 kg of product, with a yield of 85%.

[0118] NMR and mass spectrometry data are as follows: ¹H NMR (400 MHz, CDCl₃): 7.40 (dd, ¹H), 6.70 (dd, ¹H), 4.53 (t, ¹H), 3.99 (s, ³H), 3.81 (d, ²H), 3.72 (s, ³H). MS: m / z = 272.3 (M+H) + .

[0119] Example 2

[0120] Preparation of compounds with the structural formula of formula III.

[0121] Compound II (5 kg, 18.4 mol), triethylamine (3.7 kg, 36.9 mol), methanesulfonic anhydride (4.8 kg, 27.6 mol), and DCM (50 L) were added to a 100 L mechanically stirred reactor and reacted at 35–40 °C for 20 hours.

[0122] Post-processing: Water (10L) was added to the reaction solution at room temperature and stirred for 15 minutes. The organic phase was then separated and concentrated under vacuum to obtain 3.5kg of product, with a yield of 80%.

[0123] NMR and mass spectrometry data are as follows: ¹H NMR (400 MHz, CDCl₃): 6.58 (dd, ¹H), 6.53 (dd, ¹H), 4.37 (t, ¹H), 3.72 (s, ³H), 3.56 (d, ²H). MS: m / z = 340.2 (M+H) + .

[0124] Example 3

[0125] Preparation of compounds with the structural formula of formula IV.

[0126] Compound III (3.5 kg, 14.6 mol) and THF (35 L) were added to a 100 L mechanically stirred reactor. NaH (0.7 kg, 17.52 mol) was added in portions at 20–25 °C. Chloroacetyl chloride (2 kg, 17.52 mol) was added dropwise at room temperature. The reaction was allowed to proceed for 20 h at room temperature after the addition was complete. Water (7 L) was added dropwise to quench the reaction. EA (14 L) was then added, and the mixture was stirred for 15 min. The organic phase was separated and concentrated under vacuum to obtain 3.8 kg of product, with a yield of 82%.

[0127] NMR and mass spectrometry data are as follows: ¹H NMR (400MHz, CDCl₃): 6.58 (dd, ¹H), 6.53 (dd, ¹H), 4.37 (t, ¹H), 3.72 (s, ³H), 3.60 (s, ²H), 3.56 (d, ²H). MS: m / z = 316.7 (M+H) + .

[0128] Example 4

[0129] Preparation of compounds with the structural formula as shown in formula V.

[0130] Compound IV (2 kg, 6.34 mol), methanol (10 L), and palladium on carbon (0.2 kg) were added to a 20 L hydrogenation reactor. Hydrogen gas was introduced to replace the product. The reaction was carried out at 20-25 °C and 0.5 MPa for 20 h. The mixture was then filtered, and the filtrate was concentrated to dryness to obtain 1.5 kg of product, with a yield of 95%.

[0131] NMR and mass spectrometry data are as follows: ¹H NMR (400 MHz, CDCl₃): 7.75 (d, ¹H), 6.60 (d, ¹H), 4.37 (t, ¹H), 3.90 (s, 2H), 3.72 (s, 3H), 3.56 (d, 2H). MS: m / z = 250.2 (M+H) + .

[0132] Example 5

[0133] Preparation of compounds with the structural formula of formula VI.

[0134] Compound V (1.5 kg, 6 mol) and methanol (7.5 L) were added to a mechanically stirred 50 L reactor. Sodium borohydride (455 g, 12 mol) was added in portions at 20–25 °C, and the reaction was allowed to proceed for 3 h. The reaction was quenched by adding 15 L of water, and ethyl acetate (6 L) was added. The mixture was stirred for 15 min, extracted, and the organic phase was concentrated under vacuum to give 817 g of product, with a yield of 92%.

[0135] NMR and mass spectrometry data are as follows: ¹H NMR (400 MHz, CDCl₃): 7.75 (d, ¹H), 6.60 (d, ¹H), 4.37 (m, ¹H), 3.90 (s, 2H), 3.74 (d, 2H), 3.56 (d, 2H). MS: m / z = 222.2 (M+H) + .

[0136] Example 6

[0137] Preparation of compounds with the structural formula of formula VII.

[0138] Compound VI (800 g, 3.6 mol), DCM (16 L), and manganese dioxide (1.6 kg, 18 mol) were added to a 50 L mechanically stirred reactor. The mixture was reacted at room temperature for 3 h, filtered, and the supernatant was concentrated under vacuum to dryness, yielding 733 g of product, with a yield of 93%.

[0139] NMR and mass spectrometry data are as follows: ¹H NMR (400 MHz, CDCl₃): 7.75 (d, ¹H), 7.07 (s, ¹H), 6.60 (d, ¹H), 4.37 (m, ¹H), 3.74 (d, 2H), 3.56 (d, 2H). MS: m / z = 220.2 (M+H) + .

[0140] Example 7

[0141] Preparation of compounds with the structural formula as shown in Formula VIII.

[0142] Compound VII (700 g, 3.2 mol), DCM (7 L), and triethylamine (648 g, 6.4 mol) were added to a 20 L mechanically stirred reactor. The mixture was cooled to 0–5 °C, and methanesulfonyl chloride (550 g, 4.8 mol) was added dropwise. The reaction was carried out for 0.5 h, and water (1.4 L) was added. The mixture was stirred for 15 min and separated. The organic phase was concentrated under vacuum to dryness, yielding 856 g of product, with a yield of 90%.

[0143] NMR and mass spectrometry data are as follows: ¹H NMR (400 MHz, CDCl₃): 7.75 (d, ¹H), 7.07 (s, ¹H), 6.60 (d, ¹H), 4.37 (m, ¹H), 4.13 (d, 2H), 3.56 (d, 2H), 3.04 (s, 3H). MS: m / z = 298.3 (M+H) + .

[0144] Example 8

[0145] Preparation of compounds with the structural formula as shown in Formula IX.

[0146] Compound VIII (850 g, 2.86 mol), DCM (8.5 L), triethylamine (579 g, 5.72 mol), and N-Boc-piperazine (573 g, 2.86 mol) were added to a 20 L mechanically stirred reactor. The mixture was heated to 35–40 °C and reacted for 20 h. The mixture was then cooled to room temperature, and water (1.4 L) was added. The mixture was stirred for 15 min and separated. The organic phase was concentrated under vacuum to dryness, yielding 942 g of product, with a yield of 82%.

[0147] 1H NMR (400MHz, CDCl3) 1H NMR: 7.75 (d,1H), 7.07 (s,1H), 6.60 (d,1H), 5.53 (s,1H), 4.37 (m,1H), 3.64 (d,2H), 3.56 (d,2H), 3.00 (m,4H), 2.90 (m,1H), 1.74 (m,4H), 1.43 (s,9H). MS: m / z=402.5 (M+H) + .

[0148] Example 9

[0149] Preparation of compounds with the structural formula X.

[0150] Compound IX (900 g, 2.24 mol) and DCM (4.5 L) were added to a 20 L mechanically stirred reactor. Trifluoroacetic acid (511 g, 4.48 mol) was slowly added dropwise at room temperature. The reaction was carried out at room temperature for 3 h. The pH was adjusted to 9 to 10 by adding 10% sodium carbonate solution. The mixture was stirred for 15 min and separated. The organic phase was concentrated under vacuum to dryness, yielding 628 g of product, with a yield of 93%.

[0151] 1H NMR (400MHz, CDCl3) 1H NMR: 7.75 (d,1H), 7.07 (s,1H), 6.60 (d,1H), 4.37 (m,1H), 3.64 (d,2H), 3.56 (d,2H), 3.00 (m,4H), 2.73 (m,1H), 1.74 (m,4H). MS: m / z=302.4 (M+H) + .

[0152] Example 10

[0153] Preparation of compounds with the structural formula as shown in formula XI.

[0154] Compound X (600 g, 1.99 mol), ethanol (3 L), and 3,4-dihydro-2H-pyrano[2,3-C]pyridine-6-carboxaldehyde (325 g, 1.99 mol) were added to a 20 L mechanically stirred reactor. Triacetylborohydride sodium (844 g, 3.98 mol) was added in portions. The reaction was carried out at room temperature for 3 h. Water (6 L) was added to quench the reaction. Then, 2.4 L of ethyl acetate was added and stirred for 15 min. The mixture was separated and the organic phase was concentrated to dryness under vacuum. The crude product was dissolved in ethyl acetate (600 mL). Heptane (3 L) was slowly added dropwise to precipitate the product. After stirring for 2 h, the mixture was filtered to obtain 723 g of product, with a yield of 81%.

[0155] 1H NMR (400MHz, CDCl3) 8.03 (s, 1H), 7.77 (s, 1H), 7.72 (d, 1H), 6.93 (s, 1H), 6.34 (d, 1H), 4.97-5.03 (m, 1H), 4.48-4.52 (m, 1H), 4.32-4.37 (m, 1H),4.16-4.18 (m, 2H),3.74 (s, 2H),3.07-3.11 (m, 1H),2.91 (m, 1H),2.62-2.74 (m, 4H),2.45-2.52 (m, 1H),2.14-2.34 (m, 2H),1.96-2.01 (m, 2H),1.78-1.86 (m, 2H),1.28-1.40 (m, 2H). MS: m / z=449.3 (M+H) + .

[0156] 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 of gipodacin, characterized in that, The structural formula of the intermediate compound A is shown in Formula II: 。 2. A method for preparing intermediate compound A as described in claim 1, characterized in that, The intermediate compound with the structural formula of Formula I was subjected to a substitution reaction with L-serine methyl ester hydrochloride to obtain the structural formula of Formula II. The reaction route is as follows: 。 3. The preparation method according to claim 2, characterized in that, Includes one or more of the following features: The substitution reaction uses an organic solvent, which is selected from one or more of ethanol and DMF. The substitution reaction also uses a base, which is selected from one or more of potassium carbonate, sodium acetate, and triethylamine; The reaction temperature for the substitution reaction is 60~78℃; The substitution reaction also includes a post-processing step, which includes solvent extraction to obtain an organic phase followed by concentration. The molar ratio of the compound with the structural formula as described in Formula I to L-serine methyl ester hydrochloride is 1:(0.9~1.2).

4. An intermediate compound B of gipodacin, characterized in that, The structural formula of the intermediate compound B is shown in Formula III: 。 5. The method for preparing intermediate compound B according to claim 4, characterized in that: The compound with structural formula II was subjected to a cyclization reaction with methanesulfonic anhydride to obtain the intermediate compound with structural formula III. The reaction route is as follows: 。 6. The preparation method according to claim 5, characterized in that, Includes one or more of the following features: The cyclization reaction is carried out in an organic solvent selected from one or more of acetonitrile and DCM. The ring-closing reaction is carried out under alkaline conditions, wherein the base is selected from one or more of potassium carbonate, sodium acetate, and triethylamine; The reaction temperature for the ring-closure reaction is 30–40 °C. The cyclization reaction also includes a post-processing step, which includes extraction with an extraction reagent followed by separation to obtain the organic phase and concentration. The molar ratio of the compound described in Formula II to methanesulfonic acid anhydride is 1:1~2.

7. An intermediate compound C of gipodacin, characterized in that, The structural formula of the intermediate compound C is shown in Formula IV: 。 8. The method for preparing intermediate compound C according to claim 7, characterized in that, The compound with the structural formula of Formula III as described in claim 4 is subjected to a substitution reaction with chloroacetyl chloride to obtain the intermediate compound with the structural formula of Formula IV. The reaction route is as follows: 。 9. The method for preparing intermediate compound C according to claim 8, characterized in that, Includes one or more of the following features: The substitution reaction uses an organic solvent, which is selected from one or more of toluene and THF. The substitution reaction is carried out under alkaline conditions, wherein the base is selected from one or more of n-butyllithium, potassium tert-butoxide, and sodium hydrogen; The reaction temperature for the substitution reaction is 0~50℃; The substitution reaction also includes a post-processing step, which includes extraction with an extraction reagent followed by separation to obtain an aqueous phase, and concentration. The molar ratio of the compound with the structural formula as described in Formula III to chloroacetyl chloride is 1:1 to 1.

5. The molar ratio of the compound with the structural formula as described in Formula III to sodium hydrogen is 1:1 to 1.

5.

10. An intermediate compound D of gipodacin, characterized in that, The structural formula of the intermediate compound D is shown in Formula V: 。 11. The method for preparing intermediate compound D according to claim 10, characterized in that, The compound with structural formula IV was subjected to a cyclization reaction with hydrogen to obtain the intermediate compound with structural formula V. The reaction route is as follows: 。 12. The preparation method according to claim 11, characterized in that, Includes one or more of the following features: An organic solvent is used in the cyclization reaction, and the organic solvent is selected from one or more of methanol and THF. The cyclization reaction is carried out with a catalyst, which is selected from one or more of palladium on carbon or Raney nickel; The reaction temperature for cyclization is 20~40℃; The cyclization reaction also includes post-processing steps, such as filtration and concentration.

13. A method for synthesizing intermediate compound E using intermediate compound D of gipodarine as described in claim 10, characterized in that, The intermediate compound with the structural formula as shown in Formula V was subjected to a reduction reaction with sodium borohydride or potassium borohydride to obtain the intermediate compound with the structural formula as shown in Formula VI. The reaction route is as follows: 。 14. The method according to claim 13, characterized in that, Includes one or more of the following features: The reduction reaction also uses a reaction medium, which is selected from one or both of THF and methanol; The temperature for the reduction reaction is 10–50℃; After the reduction reaction is completed, a post-processing step is also included, which includes extraction and concentration. The molar ratio of the compound with the structure shown in Formula V to sodium borohydride or potassium borohydride is 1:1.9~2.5.

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