A method for purifying a key intermediate of cabotegravir

Abstract

This invention provides a purification method for compound I, a key intermediate of capecitabine. The crude compound I is dissolved in an organic solvent, stirred at a first temperature, and primary tar is removed. Water is added at room temperature, and the pH is adjusted to alkaline with alkali to remove secondary tar. The organic phase is then concentrated and recrystallized. Compared to existing technologies or traditional column chromatography processes, the purification method provided by this invention significantly improves product purity, removes tar-like substances and impurities of similar polarity generated during preparation, ensuring that the content of the toxic impurity methyl methanesulfonate in the intermediate is less than 1.0 ppm, yielding a white solid compound I with a purity ≥99%. This method is suitable for large-scale industrial production, avoids column chromatography separation, is low-cost, and environmentally friendly.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical industry, and specifically relates to a purification method for a key intermediate of cartetravir. Background Technology

[0002] Cabotegravir is a compound with HIV integrase inhibitory activity, and its structural formula is shown below:

[0003]

[0004] Currently, there are two main reported synthetic routes for cartelapvir. CN104788367A discloses a method for synthesizing cartelapvir, using compound 1 as the starting material, through cyclization, bromination, amidation, and finally hydrogenation to obtain cartelapvir. The synthetic route is as follows:

[0005]

[0006] CN101212903B discloses another synthetic method, which involves first amidation, then cyclization, and finally hydrogenation to obtain capecitabine. The synthetic route is as follows:

[0007]

[0008] Both methods above utilize a carterapir intermediate compound of formula I, with the following structural formula:

[0009]

[0010] Compound I, a key intermediate in the synthesis of capecitabine, directly affects the purity and yield of capecitabine due to its purity and impurity content. CN101212903B purified compound I using silica gel column chromatography, yielding a glassy compound with a 92% yield. This invention uses the method of CN101212903B to prepare compound I from compound 5. It was found that compound 5 is an oily or waxy solid, unstable, and prone to deterioration. After the reaction, a dark brown solution was obtained. After treatment with diatomaceous earth, a yellowish-brown solution was obtained. After vacuum solvent removal and purification by silica gel column chromatography, the obtained compound I showed a purity of only about 93.2%. HPLC showed impurities at RRTs of 0.91 and 0.97, with retention times similar to those of compound I, indicating that their polarity is similar to that of compound I, making them difficult to remove by conventional column chromatography. In industrial-scale production, the glassy compound I easily transforms into a viscous oily substance upon stirring and high-temperature operation. In industrial production, viscous, oily substances not only hinder the quality control of intermediates but also significantly impact subsequent synthesis steps. Therefore, they are unsuitable as intermediates for separation, storage, and transportation in the production of APIs. Consequently, it is necessary to prepare a compound of formula I with high purity and properties suitable for use as an intermediate in the production of capecitabine API. Summary of the Invention

[0011] The first aspect of this invention provides a method for purifying a compound of formula I, comprising the following steps:

[0012] The crude product of Formula I was dissolved in an organic solvent, stirred at a first temperature, and the primary tar was removed; water was added at room temperature, the pH was adjusted to alkaline with alkali, the secondary tar was removed, the organic phase was concentrated, and then recrystallized.

[0013] In some embodiments, the organic solvent is one or more of toluene, ethyl acetate, and xylene, preferably toluene.

[0014] In some embodiments, the mass-to-volume ratio (g / mL) of the crude compound of Formula I to the organic solvent is 1:0.5 to 100; preferably 1:5 to 20; more preferably 1:10.

[0015] In some embodiments, the first temperature is 0–120°C (e.g., 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, or any value or range thereof); preferably, the first temperature is 40–100°C (e.g., 40°C, 45°C, 50°C, 55°C, 60°C, 70°C, 80°C, 90°C, 100°C, or any value or range thereof); more preferably, the first temperature is 60–100°C (e.g., 60°C, 70°C, 80°C, 90°C, 100°C, or any value or range thereof).

[0016] In some embodiments, the stirring time is 2 to 120 minutes (e.g., 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 65 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes, or any value or range thereof); preferably, the stirring time is 15 to 90 minutes (e.g., 15 minutes, 20 minutes, 25 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 65 minutes, 70 minutes, 80 minutes, 90 minutes, or any value or range thereof); more preferably, the stirring time is 30 to 60 minutes (e.g., 30 minutes, 40 minutes, 50 minutes, or 60 minutes, or any value or range thereof).

[0017] In some embodiments, the base is an aqueous solution of an inorganic base; preferably, the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, calcium hydroxide, or magnesium hydroxide; more preferably, the inorganic base is sodium hydroxide; the mass percentage concentration of the aqueous solution is 10% to 50% (e.g., 10%, 20%, 25%, 30%, 35%, 40%, 50%, or any value or range thereof).

[0018] In some embodiments, the volume ratio of the added water to the organic solvent is 1:0.01 to 100; preferably, the volume ratio of the added water to the organic solvent is 1:1 to 20; more preferably, the volume ratio of the added water to the organic solvent is 1:1 to 5 (e.g., 1:1, 1:2, 1:3, 1:4, 1:5 or any value or range thereof).

[0019] In some embodiments, adjusting the pH to alkaline means adjusting the pH to ≥13.

[0020] In some embodiments, the recrystallization includes the following steps: adding a crystallization solvent, heating to dissolve, holding at the temperature, then gradually cooling to crystallize, filtering, and drying under reduced pressure.

[0021] In some embodiments, the crystallization solvent is a mixture of alkane solvents and other solvents, wherein the alkane solvent is selected from one or more of n-heptane, cyclohexane, or n-hexane, preferably n-heptane; the other solvents are selected from one or more of ether solvents or aromatic hydrocarbon solvents, wherein the ether solvent is selected from methyl tert-butyl ether, tetrahydrofuran, 2,5-dimethyltetrahydrofuran, 1,4-dioxane, or isopropyl ether; the aromatic hydrocarbon solvent is selected from benzene, toluene, or xylene; preferably, the other solvents are selected from tetrahydrofuran, toluene, or 1,4-dioxane.

[0022] In some embodiments, the volume ratio of the alkane solvent to the other solvent is 1:1 to 10; preferably 1:1 to 2.

[0023] In some preferred embodiments, the crystallization solvent is selected from a binary system of tetrahydrofuran and n-heptane, toluene and n-heptane, or 1,4-dioxane and n-heptane mixed in any proportion; more preferably, the volume ratio of the crystallization solvent tetrahydrofuran and n-heptane, toluene and n-heptane, or 1,4-dioxane and n-heptane is 1:1 to 10; most preferably, the volume ratio of the crystallization solvent tetrahydrofuran and n-heptane, toluene and n-heptane, or 1,4-dioxane and n-heptane is 1:1 to 2 (e.g., 1:1, 1:1.5, 1:2 or any value or range thereof).

[0024] In some embodiments, the temperature for heating and melting is 30–100°C; preferably 50–70°C; more preferably 55–60°C.

[0025] In some embodiments, the heat preservation time is 10 to 180 minutes; preferably 10 to 120 minutes; more preferably 10 to 60 minutes; and most preferably 30 to 60 minutes.

[0026] In some embodiments, the gradient cooling rate is 0.5–40 °C / h (e.g., 0.5 °C / h, 2 °C / h, 5 °C / h, 6 °C / h, 7 °C / h, 8 °C / h, 9 °C / h, 10 °C / h, 15 °C, 20 °C / h, 25 °C / h, 30 °C / h, 35 °C / h, 40 °C / h or any value or range thereof); preferably 10–30 °C / h (e.g., 10 °C / h, 20 °C / h, 25 °C / h, 30 °C / h or any value or range thereof); more preferably 10–20 °C / h (e.g., 10 °C / h, 15 °C / h, 20 °C / h or any value or range thereof).

[0027] In some embodiments, the crystallization temperature is -20 to 50°C; preferably, it is -10 to 20°C; more preferably, it is 0 to 10°C; and most preferably, it is 0 to 5°C.

[0028] A second aspect of the present invention provides a compound of formula I, wherein the compound has an HPLC purity of ≥99% and is an off-white solid.

[0029] In some embodiments, the Formula I compound contains methyl methanesulfonate impurity at a content of ≤60 ppm, impurity A at a content of ≤0.1% with an RRT of approximately 0.91, and impurity B at a content of ≤0.1% with an RRT of approximately 0.97.

[0030] In some embodiments, the content of methyl methanesulfonate impurities in the compound of Formula I is ≤2.5 ppm; more preferably, the content of methyl methanesulfonate impurities is ≤1.0 ppm.

[0031] A third aspect of the present invention provides a carterapvir, which is prepared from the compound of formula I described in the second aspect of the present invention.

[0032] The method for purifying compound I provided by this invention, and the specific process flow can be found in the following reference. Figure 1 Compared to existing technologies or traditional column chromatography processes, the purification method provided by this invention can significantly improve product purity, remove tar-like substances and impurities of similar polarity generated during the preparation process, and reduce the content of the toxic impurity methyl methanesulfonate in the intermediate to less than 1.0 ppm, obtaining a white solid compound of formula I with a purity ≥99%. This method is suitable for large-scale industrial production, avoids column chromatography separation, is low-cost, and environmentally friendly. Attached Figure Description

[0033] Figure 1 Schematic diagram of the purification process of compound I;

[0034] Figure 2 HPLC chromatogram of the crude compound of formula I in Example 1;

[0035] Figure 3 LC-MS spectrum of crude compound I in Example 1;

[0036] Figure 4 LC-MS spectrum of impurity A with RRT = 0.91;

[0037] Figure 5 LC-MS spectrum of impurity B with RRT = 0.97;

[0038] Figure 6 Example 4: HPLC chromatogram of the purified compound of formula I. Detailed Implementation

[0039] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

[0040] The terms “comprising,” “including,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other elements or method steps not listed. In this invention, “optional,” “any,” or “any” means that an event or condition subsequently described may or may not occur, and the description includes both the occurrence and non-occurrence of that event or condition.

[0041] The "medicine" described in this invention refers to a substance used to prevent, treat, and diagnose diseases. It can be a natural chemical substance and its preparation, a synthetic compound and its preparation, or a recombinant protein, antibody, and its preparation formed by bioengineering.

[0042] In this invention, all figures disclosed herein are approximate values, regardless of whether the words "approximately" or "about" are used. Based on the disclosed figures, the value of each figure may vary by less than ±10% or by a difference that is considered reasonable by those skilled in the art, such as ±1%, ±2%, ±3%, ±4%, or ±5%.

[0043] With regard to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Every smaller range between any stated value or intermediate value within a stated range, and any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0044] In this invention, unless otherwise specified, all percentages (%) refer to mass percentages.

[0045] The compound of formula I in this invention can be prepared by referring to the following method:

[0046]

[0047] In this invention, "crude product" refers to a substance that has not undergone further purification during the synthesis process. These substances may contain various impurities, including unreacted raw materials, byproducts, solvents, and other impurities. "Crude product of Formula I compound" in this invention refers to a substance obtained after preliminary purification during the synthesis of Formula I compound, including compound I and impurities. Impurities include, but are not limited to, impurities detectable under the GC-MS and HPLC conditions of this application, such as methyl methanesulfonate impurity, impurity A with an RRT of 0.91, and impurity B with an RRT of 0.97.

[0048] In this invention, the structure of the "methyl methanesulfonate impurity" is as follows:

[0049]

[0050] In this invention, the "crude compound of formula I" refers to the compound of formula I that has not been purified by the purification method described in this invention. It can be prepared by any possible method in the art, such as the methods described in CN104788367A and CN101212903B.

[0051] In this invention, "pure product" refers to a product with extremely low impurity content obtained after purification of the crude product. In this invention, "pure Formula I compound" refers to a Formula I compound with a purity ≥ 99% obtained by purification using the purification method described in this invention.

[0052] In this invention, "tar" refers to a dark, viscous substance produced during a chemical reaction, the composition of which may be complex. The terms "primary," "secondary," "first," and "secondary" are used only to distinguish batches and do not imply any other substances containing tar. For example, primary tar refers to the tar produced in step (a), and secondary tar refers to the tar produced in step (b).

[0053] In this invention, "RRT" refers to the ratio of the retention time of impurity components to the retention time of compound I during HPLC detection.

[0054] In this invention, "ppm" refers to parts per million.

[0055] The abbreviations used in this invention are explained as follows:

[0056] HPLC: High Performance Liquid Chromatography

[0057] LC-MS: Liquid chromatography-mass spectrometry

[0058] DMF: N,N-dimethylformamide

[0059] DMAC: Dimethylacetamide

[0060] GC-MS: Gas Chromatography-Mass Spectrometry

[0061] HPLC external standard method: Accurately weigh (measure) the reference standard and the test sample, prepare solutions, accurately take a certain amount of each, inject them, record the chromatogram, measure the peak area (or peak height) of the analyte in the reference standard solution and the test sample solution, and calculate the content according to the prescribed method.

[0062] The HPLC detection method used in this invention is as follows:

[0063]

[0064]

[0065] In this invention, methyl methanesulfonate impurities were detected using GC-MS, and the specific analytical method is as follows:

[0066]

[0067] For experiments not specifically described in this embodiment, the procedures and conditions should be followed according to the conventional experimental procedures described in the literature in this field. Reagents or instruments whose manufacturers are not specified are all commercially available conventional reagent products.

[0068] The technical solution of the present invention will be further described and explained below with reference to specific embodiments.

[0069] The embodiments described herein are only a part of the embodiments of the present invention, and not all of them. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the protection scope of the present invention.

[0070] Example 1: Preparation of crude compound of formula I

[0071] In a solution of compound 4 (51.6 g, 0.1 mol) in toluene (516 mL) and acetic acid (51.6 mL), methanesulfonic acid (9.61 mg, 0.1 mol) was added at room temperature, and the mixture was stirred at room temperature for 3 hours to carry out acetal hydrolysis. After the reaction was completed, the mixture was cooled to 5 °C, neutralized with saturated sodium bicarbonate aqueous solution, and extracted separately after reaching pH 6–8. The solvent was removed by distillation under reduced pressure, and toluene (516 mL) was added to the resulting concentrate. Then, (S)-2-amino-1-propanol (15.02 g, 0.2 mol) and acetic acid (51.6 mL) were added at room temperature. The mixture was heated to 90 °C to carry out condensation to form an imine, which was then further cyclized to prepare compound I. After stirring for 2 hours, the reaction was completed. The reaction system contained approximately 0.9% impurity A (RRT = 0.91) and approximately 3.1% impurity B (RRT = 0.97) (quantitatively determined by LC-MS). The reaction solution was cooled to room temperature, and water (516 mL) was added. Excess methanesulfonic acid and acetic acid were removed by extraction with 516 mL of ethyl acetate. The solvent was removed by distillation under reduced pressure to obtain a yellowish-brown oily substance. 103.2 mL of toluene was added, and the mixture was heated to dissolve. The solution was then cooled to 0°C and maintained at this temperature until crystallization and filtration yielded 43.8 g of crude compound I as a brown waxy solid, with a purity of 79.18% and a yield of 88.39%. (Purity details are provided in the original text.) Figure 2 The LC-MS spectra of impurities A and B in the crude product of compound I are shown in [reference needed]. Figure 3 Impurity A ( Figure 4 ): ES-API m / z: 496.1 [M+H]+. Impurity B( Figure 5 ): ES-API m / z:496.1[M+H]+.

[0072] Example 2: Screening for suitable organic solvents for tar removal

[0073] At room temperature, 50 mg of crude compound I was added to an organic solvent, kept at 0–120 °C, and shaken or stirred for 30–60 min to observe the dissolution of crude compound I. After keeping at this temperature for 10–60 min, the presence of brown tar-like precipitate was observed. The results are shown in Table 1.

[0074] Table 1

[0075]

[0076]

[0077] The results showed that the brown tar encapsulated in the crude compound of Formula I could only be removed by very limited solvents, especially toluene. During the experiment, brown tar-like substances precipitated out. After separation, the supernatant was light yellow. The separated brown tar-like substances were detected by HPLC external standard method, and the results showed that they contained a small amount of Formula I compound.

[0078] Example 3: Screening of crystallization solvents

[0079] At room temperature, 50 mg of the crude compound of formula I (after removing tar) was added to solvent 1 and stirred. Then, solvent 2 was added, and the temperature was raised to 30–100 °C and maintained for 10–30 minutes. The temperature was then lowered to 0–10 °C at a rate of 20 °C / h to observe the precipitation. The results are shown in Table 2.

[0080] Table 2

[0081] Solvent 1 Solvent 2 Solvent 1 / Solvent 2 (volume ratio) result Tetrahydrofuran n-Heptane 1:1 A large amount of off-white solid precipitated Toluene n-Heptane 1:1 A large amount of off-white solid precipitated 1,4-Dioxane n-Heptane 1:1 A large amount of off-white solid precipitated methanol n-Heptane 1:1 Unprecipitated ethanol n-Heptane 1:1 Unprecipitated Isopropanol n-Heptane 1:1 Unprecipitated Ethyl acetate n-Heptane 1:1 Unprecipitated acetone n-Heptane 1:1 Unprecipitated Acetonitrile n-Heptane 1:1 Layering, without crystallization dichloromethane n-Heptane 1:1 Layering, without crystallization Toluene / / Precipitated white solid Tetrahydrofuran / / A small amount of off-white solid precipitated 1,4-Dioxane / / Unprecipitated Ethyl acetate / / Unprecipitated n-Heptane / / Undissolved methanol / / Unprecipitated ethanol / / Unprecipitated Isopropanol / / Unprecipitated Ethyl acetate / / Unprecipitated acetone / / Unprecipitated Acetonitrile / / Unprecipitated dichloromethane / / Unprecipitated

[0082] Example 4: Purification of crude compound of formula I

[0083] At room temperature, 1 g of the crude compound of formula I obtained in Example 1 was added to 10 mL of toluene and dissolved to obtain a clear, yellowish-brown liquid. The mixture was heated to 60 °C and stirred for 30-60 min, during which a black oily substance gradually precipitated. Stirring was stopped, and the mixture was kept at 60-80 °C for 15-30 min. After standing, the mixture was separated, and the lower layer of black oily substance was removed. The temperature was lowered to 10-30 °C, and 10 mL of water was added to the toluene phase. 30% sodium hydroxide solution was added dropwise while stirring to adjust the pH of the aqueous phase to ≥13. During this process, a tar-like substance precipitated in the intermediate layer. The system was filtered to remove the black oily substance. The system was allowed to stand and separated, and the aqueous phase was removed. The purity of the toluene phase was 87.19%, and it was a light yellow, transparent, and clear liquid. The organic phase was distilled under reduced pressure. At room temperature, 10 mL of tetrahydrofuran was added to the reaction flask and stirred until dissolved. 10 mL of n-heptane was added, and the mixture was heated to 55-60 °C and kept at this temperature for 0.5-1 hour. The temperature was then slowly lowered to 0-5 °C at a rate of 15 °C / hour, resulting in the precipitation of a large amount of solid. The system was filtered, and 10 mL of n-heptane was added to the reaction flask to wash the solid. The filter cake was dried under reduced pressure for 16 hours to obtain 0.91 g of pure compound I as an off-white solid. The purity was 99.72%, and the yield was 91%. (Purity details are provided in the original text.) Figure 6 .

[0084] Example 5: Purification of crude compound of formula I

[0085] At room temperature, 1 g of the crude compound of formula I obtained in Example 1 was added to 10 mL of toluene and dissolved to obtain a clear, yellowish-brown liquid. The mixture was heated to 60 °C and stirred for 30-60 min, during which a black oily substance gradually precipitated. Stirring was stopped, and the mixture was kept at 60-80 °C for 15-30 min. After standing, the mixture was separated, and the lower layer of black oily substance was removed. The mixture was cooled to 10-30 °C, and 10 mL of water was added to the toluene phase. 30% sodium hydroxide solution was added dropwise with stirring to adjust the pH of the aqueous phase to ≥13. During this process, a tar-like substance precipitated in the intermediate layer. The system was filtered to remove the black oily substance. The system was allowed to stand and separated, and the aqueous phase was removed. The purity of the toluene phase was 87.19%, and it was a light yellow, transparent, and clear liquid. The organic phase was distilled under reduced pressure. At room temperature, 10 mL of toluene was added to the reaction flask and stirred until dissolved. 10 mL of n-heptane was added, and the mixture was heated to 55-60 °C and kept at this temperature for 0.5-1 hour. The mixture was then slowly cooled to 0-5 °C at a rate of 15 °C / hour, during which a large amount of solid precipitated. The system was filtered, and 10 mL of n-heptane was added to the reaction flask to wash the solid. The filter cake was dried under reduced pressure for 16 hours to obtain 0.86 g of pure compound I as an off-white solid. The purity was 99.21%, and the yield was 86%.

[0086] Example 6: Purification of crude compound of formula I

[0087] At room temperature, 1 g of the crude compound of formula I obtained in Example 1 was added to 10 mL of ethyl acetate to dissolve it, resulting in a clear, yellowish-brown liquid. The mixture was heated to 60 °C and stirred for 30-60 min, during which a small amount of black oily substance precipitated. Stirring was stopped, and the mixture was kept at 60-80 °C for 15-30 min. After standing, the mixture was separated, and the lower layer of black oily substance was removed. The mixture was then cooled to 10-30 °C, and 10 mL of water was added to the ethyl acetate phase. 30% sodium hydroxide solution was added dropwise while stirring to adjust the pH of the aqueous phase to ≥13. During this process, a small amount of tar-like substance precipitated in the intermediate layer. The system was filtered to remove the black oily substance. The system was then allowed to stand and separated, and the aqueous phase was removed. The purity of the ethyl acetate phase was 83.36%, and it was a light yellow, transparent, and clear liquid. Organic phase was distilled under reduced pressure. At room temperature, 10 mL of 1,4-dioxane was added to the reaction flask and stirred until dissolved. 10 mL of n-heptane was added, and the mixture was heated to 55–60 °C and maintained at this temperature for 0.5–1 hour. The temperature was then slowly lowered to 0–5 °C at a rate of 15 °C / hour, causing a solid to precipitate. The system was filtered, and the solid was washed with 10 mL of n-heptane. The filter cake was dried under reduced pressure for 16 hours to obtain 0.71 g of pure compound I as a white solid. The purity was 99.22%, and the yield was 76%.

[0088] Comparative Example 1: Preparation of purified compound I according to patent CN101212903B

[0089] To a solution of compound 5 (510 mg, 1.08 mmol) in dichloroethane (20 mL), (S)-2-amino-1-propanol (0.17 mL, 2.17 mmol) and 10 drops of glacial acetic acid were added. The resulting solution was heated under reflux for 2 hours. After cooling, diatomaceous earth was added to the mixture, the solvent was removed under vacuum, and the substance was purified by silica gel chromatography (2% CH3OH / CH2Cl2, gradient elution) to give 500 mg of compound I as a glassy substance with a purity of 93.2% and a yield of 93%.

[0090] Comparative Example 2:

[0091] At room temperature, 1 g of the crude compound of formula I obtained in Example 1 was added to 10 mL of ethyl acetate to dissolve it, resulting in a clear, yellowish-brown liquid. The mixture was heated to 60 °C and stirred for 30-60 min, during which a small amount of black oily substance precipitated. Stirring was stopped, and the mixture was kept at 60-80 °C for 15-30 min. After standing and separating the layers, the lower layer of black oily substance was removed. The mixture was then cooled to 10-30 °C, and 10 mL of water was added to the ethyl acetate phase. 30% sodium hydroxide solution was added dropwise while stirring to adjust the pH of the aqueous phase to ≥13. During this process, a small amount of tar-like substance precipitated in the intermediate layer. The system was filtered to remove the black oily substance. The system was allowed to stand and separated, and the aqueous phase was removed. The ethyl acetate was distilled under reduced pressure. At room temperature, 5 mL of tetrahydrofuran was added to the reaction flask, and the mixture was stirred and heated to 55-60 °C to dissolve it. The mixture was kept at this temperature for 0.5-1 hour, and then slowly cooled to 0-5 °C at a rate of 15 °C / hour, during which time a solid precipitated. The system was filtered, and 2 mL of cold tetrahydrofuran was added to the reaction flask to wash the solid. The filter cake was dried under reduced pressure for 16 hours to obtain 0.85 g of pure compound I as an off-white solid. The purity was 91.00%, and the yield was 85%.

[0092] Comparative Example 3:

[0093] At room temperature, 1 g of the crude compound of formula I obtained in Example 1 was added to 10 mL of ethyl acetate to dissolve it, resulting in a clear, yellowish-brown liquid. The mixture was heated to 60 °C and stirred for 30-60 min, during which a small amount of black oily substance precipitated. Stirring was stopped, and the mixture was kept at 60-80 °C for 15-30 min. After standing, the mixture was separated, and the lower layer of black oily substance was removed. The mixture was cooled to 10-30 °C, and 10 mL of water was added to the ethyl acetate phase. 30% sodium hydroxide solution was added dropwise while stirring to adjust the pH of the aqueous phase to ≥13. During this process, a small amount of tar-like substance precipitated in the intermediate layer. The system was filtered to remove the black oily substance. The system was allowed to stand and separated, and the aqueous phase was removed. The ethyl acetate phase was distilled under reduced pressure. At room temperature, 10 mL of tetrahydrofuran was added to the reaction flask and stirred until dissolved. 10 mL of n-heptane was added, and the mixture was heated to 55-60 °C until dissolved. The mixture was then rapidly cooled to 0-5 °C at a rate of approximately 50 °C / hour, and a solid precipitated. The system was filtered, and 10 mL of n-heptane was added to the reaction flask to wash the solid. The filter cake was dried under reduced pressure for 16 hours to obtain 0.85 g of pure compound I as an off-white solid. The purity was 98.94%, and the yield was 85%.

[0094] The purity of the Formula I compounds in Examples 1-4 and Comparative Examples 1-3 was tested, and the results are shown in Table 3:

[0095] Table 3

[0096]

[0097]

[0098] Example 7: Preparation of Cartetravir API

[0099] At room temperature, 0.4 g of pure compound I was added to 30 mL of methanol, stirred, and 0.025 g of 10% palladium on carbon was added. After the addition was complete, the mixture was purged with nitrogen three times and hydrogen three times. The temperature was raised to 40–60 °C and reacted for 2 h. The reaction was monitored until the reactants were completely reacted. The reaction system was filtered through diatomaceous earth, and 50 mL of water was added to the filtrate. The mixture was stirred and separated. The organic phase was concentrated under reduced pressure, and 5 mL of methanol was added to the concentrate. The temperature was raised to 50–60 °C and held for 2 h. The temperature was then lowered to 0 °C at a rate of 20 °C / h. The wet product was filtered and dried to obtain solid capecitabine API. The results are shown in Table 4.

[0100] Table 4

[0101]

[0102] The present invention has been described in detail above, with the aim of enabling those skilled in the art to understand and implement the invention. However, this description should not be construed as limiting the scope of protection of the invention. All equivalent changes or modifications made in accordance with the spirit and essence of the invention should be included within the scope of protection of the invention.

Claims

1. A method for purifying a key intermediate compound of cartetravir, characterized in that, Includes the following steps: The crude product of Formula I was dissolved in an organic solvent, stirred at a first temperature, and the primary tar was removed; water was added at room temperature, the pH was adjusted to alkaline with alkali, the secondary tar was removed, the organic phase was concentrated, and then recrystallized. The structure of compound I is shown below:

2. The purification method according to claim 1, characterized in that, The organic solvent is one or more of toluene, ethyl acetate, and xylene; preferably, the organic solvent is toluene; and / or the mass-to-volume ratio (g / mL) of the crude compound of Formula I to the organic solvent is 1:0.5 to 100; preferably 1:5 to 20; more preferably 1:

10.

3. The purification method according to claim 1, characterized in that, The first temperature is 0–120°C, and the stirring time is 2–120 minutes; preferably, the first temperature is 30–100°C, and the stirring time is 10–90 minutes; more preferably, the first temperature is 40–100°C, and the stirring time is 10–60 minutes.

4. The purification method according to claim 1, characterized in that, The alkali is an aqueous solution of an inorganic alkali; preferably, the inorganic alkali is one or more of sodium hydroxide, potassium hydroxide, sodium bicarbonate, calcium hydroxide, or magnesium hydroxide; more preferably, the inorganic alkali is sodium hydroxide; the mass percentage concentration of the aqueous solution is 10% to 50%; and / or the volume ratio of the added water to the organic solvent is 1:0.01 to 100; preferably, the volume ratio of the added water to the organic solvent is 1:1 to 20; more preferably, the volume ratio of the added water to the organic solvent is 1:1 to 5; and / or adjusting the pH value to alkalinity means adjusting the pH value to ≥13.

5. The purification method according to claim 1, characterized in that, The recrystallization includes the following steps: adding a crystallization solvent, heating to dissolve, maintaining the temperature, then gradually cooling to crystallize, filtering, and drying under reduced pressure.

6. The purification method according to claim 5, characterized in that, The crystallization solvent is a mixture of alkane solvents and other solvents. The alkane solvent is selected from one or more of n-heptane, cyclohexane, or n-hexane, preferably n-heptane. The other solvents are selected from one or more of ether solvents or aromatic hydrocarbon solvents. The ether solvent is selected from methyl tert-butyl ether, tetrahydrofuran, 2,5-dimethyltetrahydrofuran, 1,4-dioxane, or isopropyl ether. The aromatic hydrocarbon solvent is selected from benzene, toluene, or xylene. Preferably, the other solvents are selected from tetrahydrofuran, toluene, or 1,4-dioxane. More preferably, the volume ratio of the alkane solvent to the other solvents is 1:1 to 10. More preferably, it is 1:1 to 2.

7. The purification method according to claim 6, characterized in that, The crystallization solvent is selected from a binary system of tetrahydrofuran and n-heptane, toluene and n-heptane, or 1,4-dioxane and n-heptane mixed in any proportion; more preferably, the volume ratio of the crystallization solvent tetrahydrofuran and n-heptane, toluene and n-heptane, or 1,4-dioxane and n-heptane is 1:1 to 10; most preferably, the volume ratio of the crystallization solvent tetrahydrofuran and n-heptane, toluene and n-heptane, or 1,4-dioxane and n-heptane is 1:1 to 2; and / or the temperature for heating and dissolving is 30 to 100°C; preferably 50 to 70°C; more preferably... Preferably, the temperature is 55–60°C; and / or the holding time is 10–180 minutes; preferably 10–120 minutes; more preferably 10–60 minutes; most preferably 30–60 minutes; and / or the gradient cooling rate is 0.5–40°C / hour; preferably 5–30°C / hour; more preferably 5–20°C / hour; and / or the crystallization temperature is -20–50°C; preferably -10–20°C; more preferably 0–10°C; most preferably 0–5°C.

8. A compound of formula I, wherein the compound has an HPLC purity of ≥99% and is an off-white solid.

9. The compound according to claim 8, characterized in that, The compound of Formula I contains methyl methanesulfonate impurity at a content of ≤60ppm, impurity A at a content of ≤0.1% with an RRT of approximately 0.91, and impurity B at a content of ≤0.1% with an RRT of approximately 0.97; further, the content of methyl methanesulfonate impurity in the compound of Formula I is ≤2.5ppm; more preferably, the content of methyl methanesulfonate impurity is ≤1.0ppm.

10. A cartelapvir, which is further prepared from the compound of formula I according to claim 8.

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