Synthesis method of (3aR, 6aR)-2, 2-dimethyl tetrahydro-3aH-cyclopenta [d] [1, 3] dioxol-4 (6aH)-ketone
By optimizing the synthetic route of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one, a five-step method was adopted and the reaction conditions were optimized. This solved the problems of cumbersome process and unsuitability for large-scale production in the existing technology, and achieved the production of the target product with high yield and high purity, which is suitable for large-scale application.
Patent Information
- Application Number
- CN202511185386.2
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-22
- Publication Date
- 2025-12-05
AI Technical Summary
The existing synthesis process of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one is cumbersome and not suitable for kilogram-scale scale-up processes, which limits the application range of carbocyclic nucleoside compounds.
The five-step synthetic route involves the reaction of multiple compounds under nitrogen protection and utilizes a method that eliminates the need for column chromatography purification. By employing specific solvents and catalysts and optimizing reaction conditions, the yield and purity are improved, making it suitable for large-scale production.
The synthesis process is simplified, the number of steps is reduced, the yield and purity of the compound in each step are improved, making it suitable for kilogram-scale industrial production and reducing production costs and complexity.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application relates to the technical field of organic synthesis, and more particularly to a synthesis method of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one. BACKGROUND
[0002] Viral infectious diseases such as human immunodeficiency virus, hepatitis B virus and various herpes viruses have long been a serious threat to global public health safety. Due to the rapid mutation and escape ability of viruses from host immunity, traditional vaccines and antiviral drugs often face problems such as drug resistance, side effects and limited efficacy. Therefore, developing new high-efficiency, broad-spectrum and low-toxicity antiviral drugs has always been a key direction of pharmaceutical chemistry and medical research.
[0003] Nucleosides include natural nucleosides and artificially synthesized nucleosides. Among them, artificially synthesized nucleosides can inhibit the DNA or RNA polymerase activity of viruses or host cells by changing the base or sugar group in natural nucleosides, prevent the synthesis of DNA or RNA, and kill viruses.
[0004] Abacavir is a carbocyclic nucleoside, which has been approved by the US Food and Drug Administration as an anti-HIV drug. Entecavir is a carbocyclic nucleoside with an exocyclic double bond, which has also been approved for the treatment of chronic hepatitis B virus infection. In addition, carbocyclic nucleosides have also been recently reported as antiviral drugs against smallpox virus, monkeypox virus and West Nile virus. Therefore, carbocyclic nucleosides have shown high antiviral activity in the field of antiviral drugs.
[0005] The related art discloses a carbocyclic nucleoside compound and a method for treating emerging diseases including influenza and Venezuelan equine encephalitis virus, wherein (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one is a key intermediate of the carbocyclic nucleoside compound and has important application value. In the related art, the synthesis process of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one is as follows:
[0006] However, the above synthesis process has a total of eight steps, and most of the intermediates need to be purified by column chromatography, which is relatively cumbersome and not suitable for kilogram-scale scale-up process, limiting the application range of the carbocyclic nucleoside compound. SUMMARY
[0007] In order to simplify the synthesis process of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one, expand the application range of carbocyclic nucleoside compounds, the application provides a synthesis method of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one.
[0008] In a first aspect, the application provides a synthesis method of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one, which adopts the following technical solution: A synthesis method of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one, and a synthesis route is as follows: The synthesis method comprises the following steps: S1: under nitrogen protection, D-ribose and acetone are mixed to obtain a mixture; the mixture is mixed with an acid and stirred at room temperature for 2.5-8 h to obtain a reaction solution; the pH value of the reaction solution is adjusted to 7-8, the reaction solution is filtered, and the filtrate is collected and evaporated under reduced pressure to obtain an M1 compound; S2: under nitrogen protection, the M1 compound and anhydrous tetrahydrofuran are mixed to obtain a mixture; vinylmagnesium bromide is added dropwise to the mixture at-30-25 DEG C, and the mixture is stirred at-5-25 DEG C for 16-24 h to obtain a reaction solution; the reaction solution is treated to obtain an M2 compound; S3: the M2 compound, dichloromethane and water are mixed to obtain a mixture; the temperature of the mixture is adjusted to-20-40 DEG C, sodium periodate is added, and then the mixture is stirred at room temperature for 0.6-6 h to obtain a reaction solution; water is added to the reaction solution, and then the reaction solution is extracted with an organic solvent, and the organic phase is collected and evaporated under reduced pressure to obtain an M3 compound; S4: methyltriphenylphosphonium bromide and tetrahydrofuran are mixed to obtain a methyltriphenylphosphonium bromide solution; the temperature of the methyltriphenylphosphonium bromide solution is adjusted to-10-30 DEG C, and then potassium tert-butoxide is added under a nitrogen atmosphere to obtain a reaction mixture; the reaction mixture is first stirred at room temperature for 2-6 h, then cooled to-5-5 DEG C, and finally the M3 compound is added, and after the addition is completed, the reaction mixture is stirred at room temperature for 18-24 h to obtain a reaction solution; Water is added to the reaction solution to quench the reaction, and then the reaction solution is extracted with an organic solvent, and the organic phase after extraction is collected, dried, filtered, and evaporated under reduced pressure to obtain a crude product; the crude product is purified to obtain an oil; an aromatic hydrocarbon organic solvent is added to the oil, and then the oil is evaporated under reduced pressure to obtain an M4 compound; S5: first mix 1% Grubbs 2nd generation catalyst and anhydrous dichloromethane, then add M4 compound, stir the mixture at room temperature under nitrogen atmosphere for 16-24 hours to obtain a reaction solution containing M5 compound; The reaction solution can be directly used in the next step reaction, or the reaction solution is evaporated under reduced pressure to obtain a crude product, and then the crude product is purified to obtain the M5 compound. S6: first mix the reaction solution containing M5 compound or M5 compound and dichloromethane, then add manganese dioxide to obtain a mixture; stir the mixture at room temperature for 16-24 hours to obtain a reaction solution; filter the reaction solution, collect the filtrate and evaporate under reduced pressure to obtain a crude product; and the crude product is beaten to obtain the target product.
[0009] By using the above technical solution, the reaction solution of the S5 step reaction can be treated and then used as raw material for the S6 step, or directly used as raw material for the S6 step reaction. Therefore, the synthesis process of the present application can synthesize the target product in five steps, does not need to be purified by column chromatography, can be produced to the kilogram level, and the yield and purity of the compound synthesized in each step are as high as 90% or more. Compared with the synthesis process of the target product in the related art, the process of the present application is simple in operation, convenient in post-treatment, and more suitable for large-scale industrial production.
[0010] Preferably, in the S1 step, the acid is p-toluenesulfonic acid monohydrate; and the S1 step is as follows: Under the protection of nitrogen, mix D-ribose and acetone to obtain a mixture; adjust the temperature of the mixture to be in the range of 0-10℃, then add p-toluenesulfonic acid monohydrate and 2,2-dimethoxypropane, and stir the mixture at room temperature for 2.5-6 hours to obtain a reaction solution; adjust the pH value of the reaction solution to be 7-8, filter, collect the filtrate and evaporate under reduced pressure to obtain the M1 compound.
[0011] Preferably, in the S1 step, the acid is sulfuric acid; and the S1 step is as follows: Under the protection of nitrogen, mix D-ribose and acetone to obtain a mixture; add sulfuric acid to the mixture, and stir the mixture at room temperature for 3-8 hours to obtain a reaction solution; adjust the pH value of the reaction solution to be 7-8, filter, collect the filtrate and evaporate under reduced pressure to obtain the M1 compound.
[0012] By using the above technical solution, the acid is selected to be p-toluenesulfonic acid monohydrate or sulfuric acid, and the yield and purity of the synthesized M1 compound are similar. The present application preferably uses p-toluenesulfonic acid monohydrate as the raw material for the reaction with D-ribose, because it does not release heat during the reaction, and is more suitable for large-scale production.
[0013] Preferably, the S2 step is as follows: Mixing the M1 compound and anhydrous tetrahydrofuran under nitrogen protection to obtain a mixture; adjusting the temperature of the mixture to -30 to -10℃, and then adding vinyl magnesium bromide dropwise to obtain a reaction mixture; reacting the reaction mixture at -5 to 5℃ for 16 to 24 hours to obtain a reaction liquid; adding water to the reaction liquid, then extracting with an organic solvent, collecting the organic phase and evaporating under reduced pressure to obtain the M2 compound.
[0014] Preferably, the S2 step is: Mixing the M1 compound and anhydrous tetrahydrofuran under nitrogen protection to obtain a mixture; adjusting the temperature of the mixture to -20 to 25℃, and then adding vinyl magnesium bromide dropwise to obtain a reaction mixture; reacting the reaction mixture at room temperature for 16 to 24 hours to obtain a reaction liquid; adding the reaction liquid to ice, and taking the supernatant and evaporating under reduced pressure to obtain the M2 compound.
[0015] By adopting the above technical solution, under anhydrous conditions, by adding the Grignard reagent dropwise at -20 to 25℃, and then reacting at room temperature, the reaction result is consistent with that of -30℃ dropwise, and then at -5 to 5℃, so the synthesis process of the present application has a wider reaction temperature and is more suitable for industrial production.
[0016] Preferably, in the S4 step, the aromatic hydrocarbon organic solvent is toluene.
[0017] By adopting the above technical solution, after column chromatography purification, toluene is used to form azeotropy with the concentrated liquid after passing through the column to remove water, which is beneficial to the next step reaction.
[0018] Preferably, in the S1 step, the molar ratio of D-ribose, p-toluenesulfonic acid monohydrate and 2,2-dimethoxypropane is 1:(0.01 to 0.2):(0.9 to 1.2).
[0019] Preferably, in the S2 step, the molar ratio of the M1 compound and vinyl magnesium bromide is 1:(2.5 to 4).
[0020] Preferably, in the S3 step, the molar ratio of the M2 compound and sodium periodate is 1:(1.0 to 4).
[0021] Preferably, in the S4 step, the molar ratio of the M3 compound, methyltriphenylphosphonium bromide and potassium tert-butoxide is 1:(1.0 to 2.5):(1.0 to 3).
[0022] Preferably, in the S5 step, the feeding ratio of the M4 compound and dichloromethane is 1g:(25 to 50)mL.
[0023] By adopting the above technical solution, the amount of dichloromethane added is in the above range, and the M4 compound is not easy to condense with each other, so it has higher reactivity.
[0024] Preferably, the molar ratio of the S6 step, the M5 compound and manganese dioxide is 1: (1.0-4).
[0025] In summary, the present application has the following beneficial effects: 1. The synthesis process of the present application can synthesize the target product in five steps, the process steps are short, the post-treatment is simple, and it is suitable for large-scale kilogram industrial production; 2. In the S1 step of the synthesis process of the present application, p-toluenesulfonic acid monohydrate does not release heat during the reaction process, the reaction conditions are safer, and it is more suitable for large-scale production; 3. In the S2 step of the synthesis process of the present application, under anhydrous conditions, by adding formylating reagent at -20-25℃, after the completion of dropwise addition, the reaction can be carried out at room temperature, which has a wide reaction temperature and is more suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS
[0026] Figure 1 is the HNMR chart of the M2 compound in Example 1 of the present application; Figure 2 is the HNMR chart of the M3 compound in Example 1 of the present application; Figure 3 is the HNMR chart of the M4 compound in Example 1 of the present application; Figure 4 is the HNMR chart of the M5 compound in Example 1 of the present application; Figure 5 is the HNMR chart of the M6 compound in Example 1 of the present application. DETAILED DESCRIPTION
[0027] The present application will be further described in detail below in combination with the drawings and examples.
[0028] The raw materials used in the examples of the present application are all commercially available. EXAMPLE
[0029] Example 1 A synthesis method of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one, the synthesis route is as follows:
[0030] The synthesis method of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one described above comprises the following steps: S1: S11: Under nitrogen protection, D-ribose (13.5 kg, 89.922 mol) was added to acetone (100 L), and the mixture was stirred to obtain a mixture. The temperature of the mixture was adjusted to the range of 0-10℃, and then p-toluenesulfonic acid monohydrate (0.51 kg, 2.698 mol) and 2,2-dimethoxypropane (12104.578 mL, 98.914 mol) were added. The mixture was stirred at room temperature (20-25℃) for 3 h. The reaction was monitored by TLC until it was complete, and the reaction solution was obtained. The reaction solution was clear.
[0031] S12: Add solid NaHCO3 (100.5g) to the reaction solution (100L) for neutralization, adjust the pH of the reaction solution to 7-8, filter, collect the filtrate and evaporate under reduced pressure to obtain compound M1 (15.5kg, yield 90%, purity 98%).
[0032] S2: S21: Under nitrogen protection, compound M1 (1 kg, 5.2 mol) was added to anhydrous tetrahydrofuran (8 L), and the mixture was stirred to obtain a mixture. The temperature of the mixture was adjusted to -30 °C, and vinyl magnesium bromide (1 mol / L tetrahydrofuran solution) (19 L, 287.751 mol) was added dropwise to obtain a reaction mixture. The reaction mixture was stirred at -5 to 5 °C for 16 h, and the reaction was monitored by TLC to ensure complete reaction, thus obtaining a reaction solution.
[0033] S22: Add the reaction solution to ice water (5L) and ethyl acetate (10L), stir and mix, let stand for 30 min, separate into layers, the upper layer is the supernatant, and the lower layer is the reaction solution containing the precipitate, collect the supernatant; continue to add ethyl acetate (10L) to the reaction solution, stir and mix, let stand, take the supernatant, repeat the extraction of the reaction solution twice, and collect the supernatant; finally combine the supernatants collected from each extraction.
[0034] The reaction solution containing the precipitate contained a solid. The solid was filtered through diatomaceous earth, and sodium chloride was added to the filtrate until a saturated solution was obtained. The aqueous phase was extracted twice with ethyl acetate (5L). The extracted ethyl acetate was combined and dried with sodium sulfate. After filtration, the filtrate and the combined supernatant were collected and evaporated under reduced pressure to obtain an oily liquid.
[0035] Depend on Figure 1 It can be determined that the oily liquid is compound M2 (1.4 kg, yield 96%, purity 95%).
[0036] S3: S31: Add compound M2 (100g, 458.192mmol) to a mixed solution of dichloromethane (500ml) and water (1.0L), stir and mix to obtain a mixture; adjust the temperature of the mixture to 0℃, then add sodium periodate (1409.822mL, 916.384mmol), and then stir the reaction at room temperature (20~25℃) for 40min to obtain a reaction solution.
[0037] S32: Add water (210 mL) to the reaction solution, extract three times with dichloromethane (200 mL), combine the extracted organic phases and dry with sodium sulfate, filter, collect the filtrate and evaporate under reduced pressure to obtain a yellow oily product.
[0038] Depend on Figure 2 It can be seen that the yellow oily product is compound M3 (80g, yield 93%, purity 95%).
[0039] S4: S41: Add methyltriphenylbromophos (9.5 kg, 26.5 mol) to tetrahydrofuran (16 L), stir and mix to obtain a methyltriphenylbromophos solution; adjust the temperature of the methyltriphenylbromophos solution to 0 °C, and then add potassium tert-butoxide (3.62 kg, 32.222 mol) in 10 batches under a nitrogen atmosphere to obtain a reaction mixture.
[0040] The reaction mixture was stirred at room temperature (20-25℃) for 2 hours, cooled to 0℃, and then compound M3 (2 kg, 10.741 mol) was added. The reaction mixture was exothermic during the addition process. The temperature was controlled at 0-10℃. After the addition was completed, the reaction mixture was stirred at room temperature (20-25℃) for 18 hours. The reaction was monitored by TLC until it was complete, and the reaction solution was obtained.
[0041] S42: Add water (5L) to the reaction solution and stir for 30 min to quench the reaction. Then extract three times with ethyl acetate (5L). Combine the extracted organic phases and dry them with anhydrous magnesium sulfate. Filter the mixture and collect the filtrate. Evaporate under reduced pressure to obtain the crude product.
[0042] The crude product was purified by silica gel column chromatography (eluent composed of ethyl acetate and petroleum ether in a volume ratio of 1:10) to obtain a yellow oil. Toluene (1 L) was added to the yellow oil, and the mixture was evaporated under reduced pressure to obtain the yellow oil product.
[0043] Depend on Figure 3 It can be seen that the yellow oily product is compound M4 (1.9 kg, yield 96%, purity 98%).
[0044] S5: S51: First, add 1% Grubbs 2nd generation catalyst (0.05g, 0.054mmol) to anhydrous dichloromethane (100mL), then add M4 compound (4g, 21.711mmol), stir for 16h under nitrogen atmosphere and room temperature (20-25℃), and monitor the reaction by TLC to obtain the reaction solution.
[0045] S52: Post-processing steps of the reaction solution: evaporate the reaction solution to dryness, pass the crude product through a silica gel column, and elute with petroleum ether to ethyl acetate in a ratio of 10:1 to obtain an oily product.
[0046] Depend on Figure 4 It can be seen that the oily product is compound M5 (3.2g, yield 94%, purity 96%).
[0047] S6: S61: First, add compound M5 (295 mg, 1.889 mmol) to dichloromethane (35 mL), then add manganese dioxide (558 mg, 6.3 mmol) to obtain a mixture; stir the mixture at room temperature (20-25 °C) for 16 h, and monitor the reaction by TLC until it is complete to obtain the reaction solution.
[0048] S62: Filter the reaction solution through silica gel, rinse with dichloromethane, collect the filtrate and concentrate until no liquid drips out (if it cannot be turned into a solid, cool with ice water) to obtain the crude product; slurry the crude product with petroleum ether (10 mL) for 10-24 h (10 h in the example of this application) to obtain a white solid.
[0049] Depend on Figure 5 It can be determined that the white solid is (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one (270 mg, yield 92%, purity 98%).
[0050] Example 2 A method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one differs from Example 1 in that step S1 is different.
[0051] S1: S11: Under nitrogen protection, D-ribose (1 kg, 6660.894 mmol) was added to acetone (30 L) and stirred to obtain a mixture; sulfuric acid (3 mL, 56.011 mmol) was added to the mixture at room temperature, and the mixture was stirred at room temperature (20-25 °C) for 2.5 h. The reaction was monitored by TLC until it was complete, and the reaction solution was obtained. During the reaction, the reaction solution was initially turbid and then gradually became clear.
[0052] S12: NaHCO3(110 g) was added to the reaction solution to neutralize it, and the pH of the reaction solution was adjusted to 7-8. Filtration was performed, and the filtrate was collected and evaporated under reduced pressure to obtain the M1 compound (1.3 kg, yield 89%, purity 93%).
[0053] Comparing Example 1 and Example 2, it can be seen that in the S1 step, the use of p-toluenesulfonic acid monohydrate and D-ribose to generate the M1 compound not only has higher yield and purity, but also does not generate a large amount of heat during the reaction, and is more suitable for large-scale industrial production.
[0054] Example 3 A synthesis method of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one differs from Example 1 in that the S2 step is different.
[0055] S2: S21: The M1 compound (1 kg, 5.2 mol) was added to anhydrous tetrahydrofuran (8 L) and stirred to obtain a mixture. The temperature of the mixture was adjusted to -20-25°C (in this example, -20°C), and then vinylmagnesium bromide (1 MOL / L tetrahydrofuran solution) (19 L, 287.751 mol) was added dropwise to obtain a reaction mixture. The reaction mixture was stirred at 25°C for 16 h, and TLC was used to monitor the completion of the reaction to obtain a reaction solution.
[0056] S22: Ice was added to the reaction solution, and the supernatant was extracted and evaporated under reduced pressure to obtain an oily liquid.
[0057] Detection showed that the nuclear magnetic shift data of the oily liquid were consistent with those of Figure 1 , which was the M2 compound (1.4 kg, yield 96%, purity 95%).
[0058] Comparing Example 1 and Example 3, it can be seen that in the S2 step, the dropwise addition of the Grignard reagent at -20-25°C and stirring at 25°C for 16 h has the same reaction result as the dropwise addition of the Grignard reagent at -30°C and stirring at 0°C for 16 h. Therefore, the synthesis process of the present application has a wide temperature range.
[0059] Example 4 A synthesis method of (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one differs from Example 3 in that the S22 step is different.
[0060] S22: The reaction solution was added to water, and the reaction solution formed a gelatinous mixture. The gelatinous mixture was filtered through diatomite, and the filtrate was added to sodium chloride solid to a saturated solution. The water phase was extracted twice with ethyl acetate (5 L), and the combined extracted ethyl acetate was dried with sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain an oily liquid.
[0061] The nuclear magnetic shift data of the oily liquid was consistent with that of Figure 1 , which was M2 compound (1.0 kg, yield 70%, purity 92%).
[0062] Comparing Example 3 and Example 4, it can be seen that in the S2 step, the reaction solution was added to water to form a gelatinous substance. In the actual post-treatment process, the time consumption of Example 4 was more than four times that of Example 3, the post-treatment was more complex, and the yield and purity of M2 compound decreased.
[0063] Example 5 A synthesis method of (3aR, 6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one, which is different from Example 1, is different in the S3 step.
[0064] S3: S31: The M2 compound (200 g, 916.384 mmol) was added to a mixed solution of dichloromethane (1000 ml) and water (1 L), and after stirring the mixture, the temperature of the mixture was adjusted to 0°C, and then sodium periodate (1410 mL, 2820 mmol) aqueous solution was added dropwise. Then the reaction was stirred at room temperature (20-25°C) for 40 min to obtain a reaction solution.
[0065] S32: Water (400 mL) was added to the reaction solution, which was extracted three times with dichloromethane (1 L), and the combined organic phase was dried with sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to obtain a yellow oily product.
[0066] The nuclear magnetic shift data of the yellow oily product was consistent with that of Figure 2 , which was M3 compound (163 g, yield 96%, purity 98%).
[0067] Comparing Example 1 and Example 5, it can be seen that when the molar ratio of M2 compound and sodium periodate is within a certain range, the synthesized M3 compound has high purity and yield. At the same time, in the S32 step, dichloromethane extraction is used to separate the product and other impurities in the reaction solution, which is conducive to improving the yield and purity of the product.
[0068] Example 6 A method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one, which is different from example 1 in that steps S5 and S6 are different.
[0069] S5: S51: First, 1% Grubbs 2nd generation catalyst (39.03 g, 46.028 mmol) was added to anhydrous dichloromethane (50 L), then M4 compound (1060 g, 5.7 mol) was added, and stirring was carried out at room temperature (20-25°C) under a nitrogen atmosphere for 7 h. TLC monitoring showed that the reaction was complete, and a reaction solution was obtained.
[0070] S52: It was detected that M5 compound was generated in the reaction solution. The reaction solution was not subjected to post-treatment, and the next step was directly carried out.
[0071] S6: S61: First, the reaction solution of S52 was mixed with dichloromethane (10 L), and then manganese dioxide (1.5 kg, 17 mol) was added to obtain a mixture. The mixture was stirred at room temperature (20-25°C) for 16 h, and TLC monitoring showed that the reaction was complete, and a reaction solution was obtained.
[0072] S62: The reaction solution was filtered through silica gel and rinsed with dichloromethane. The filtrate was concentrated until no liquid droplets were obtained (if it cannot become a solid, ice water cooling is used), and a crude product was obtained. The crude product was slurried with petroleum ether (3 L) for 10-24 h (10 h in this example), and a white solid was obtained.
[0073] It was detected that the nuclear magnetic shift data of the white solid were consistent with those of Figure 5 , and the white solid was (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one (500 mg, yield 53%, purity 96%).
[0074] Comparing example 1 and example 6, it can be seen that the reaction solution of step S51 does not need to be subjected to post-treatment and can be directly used for feeding in step S61. The purity of the target product synthesized in step S62 is similar. Therefore, the synthesis process of the present application has a short synthesis route and is more suitable for large-scale production.
[0075] Example 7 A method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4(6aH)-one, which is different from example 1 in that step S6 is different.
[0076] S6: S61: First, add compound M5 (1060g, 6.7mol) to dichloromethane (10.6L), then add manganese dioxide (1500g, 18mol) to obtain a mixture; stir the mixture at room temperature (20-25℃) for 16h, and monitor the reaction by TLC until it is complete to obtain the reaction solution.
[0077] S62: Filter the reaction solution through silica gel, rinse with dichloromethane, collect the filtrate and concentrate until no liquid drips out (if it cannot be turned into a solid, cool with ice water) to obtain the crude product; the crude product is slurried with petroleum ether (500 mmL) for 2 hours to obtain a white solid.
[0078] Upon testing, the NMR shift data of the white solid was found to be consistent with... Figure 5 Consistent, the white solid was (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one (962 g, yield 92%, purity 98%).
[0079] A comparison of Examples 1 and 7 shows that, under different reaction weights, the target products synthesized using the synthesis process of this application all have high yields and purity, and are therefore more suitable for large-scale production.
[0080] Comparative Example Comparative Example 1 A method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one differs from Example 1 in that steps S4 and S5 are different.
[0081] S4: S41: Add 4.8 kg of methyltriphenylbromophos (13.42 mol) to 8 L of tetrahydrofuran and stir to obtain a methyltriphenylbromophos solution; adjust the temperature of the methyltriphenylbromophos solution to 0 °C, and then add potassium tert-butoxide (1.81 kg, 16.11 mol) in 10 batches under a nitrogen atmosphere to obtain a reaction mixture.
[0082] The reaction mixture was stirred at room temperature (20-25℃) for 2 hours, cooled to 0℃, and then compound M3 (1 kg, 5.37 mol) was added. The reaction mixture was exothermic during the addition process. The temperature was controlled at 0-10℃. After the addition was completed, the reaction mixture was stirred at room temperature (20-25℃) for 18 hours. The reaction was monitored by TLC until it was complete, and the reaction solution was obtained.
[0083] S42: Add water (4L) to the reaction solution and stir for 30 min to quench the reaction. Then extract three times with ethyl acetate (4L). Combine the extracted organic phases and dry them with anhydrous magnesium sulfate. Filter the solution and collect the filtrate. Evaporate under reduced pressure to obtain the crude product.
[0084] The crude product was purified by silica gel column chromatography (eluent composed of ethyl acetate and petroleum ether mixed at a volume ratio of 1:10) to obtain a yellow oil.
[0085] It was detected that the oily liquid was the M4 compound (0.94 kg, yield 95%, purity 95%) S5: S51: First, 1% Grubbs 2nd generation catalyst (0.46 g, 0.543 mmol) was added to anhydrous dichloromethane (500 mL), then the M4 compound synthesized in S42 above (10 g, 53 mmol) was added, and stirred at room temperature (20-25°C) for 16 h under nitrogen atmosphere, and TLC monitoring showed that the raw material was completely consumed and no product was generated.
[0086] Comparing Example 1 and Comparative Example 1, although the yields and purities of the M4 compounds synthesized by both were similar, in the S42 step of Example 1, toluene was used to form azeotrope with the purified yellow oil to remove the water in the yellow oil, so that the reaction in the S51 step could proceed smoothly to generate the M5 compound.
[0087] This specific embodiment is only an explanation of the present application, and is not a limitation of the present application. Those skilled in the art can make modifications to this embodiment without creative contribution after reading the present specification, but as long as the modifications are within the scope of the claims of the present application, they are protected by the Patent Law.
Claims
1. A method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one, characterized in that, The synthesis route is as follows: The above synthesis method includes the following steps: S1: Under nitrogen protection, D-ribose and acetone were mixed to obtain a mixture; the mixture was then mixed with acid and stirred at room temperature for 2.5–8 h to obtain a reaction solution; the pH of the reaction solution was adjusted to 7–8, filtered, and the filtrate was collected and evaporated under reduced pressure to obtain compound M1; S2: Under nitrogen protection, compound M1 and anhydrous tetrahydrofuran were mixed to obtain a mixture; Grignard reagent was added dropwise to the mixture at -30 to 25°C, and the mixture was stirred at -5 to 25°C for 16 to 24 hours to obtain a reaction solution; the reaction solution was post-treated to obtain compound M2. S3: Mix M2 compound, dichloromethane, and water to obtain a mixture; adjust the temperature of the mixture to -20 to 40°C, add sodium periodate, and then stir the reaction at room temperature for 0.6 to 6 hours to obtain a reaction solution; add water to the reaction solution, then extract with an organic solvent, collect the organic phase and evaporate under reduced pressure to obtain M3 compound; S4: Methyltriphenylbromophos and tetrahydrofuran were mixed to obtain a methyltriphenylbromophos solution; the temperature of the methyltriphenylbromophos solution was adjusted to -10 to 30°C, and then potassium tert-butoxide was added under a nitrogen atmosphere to obtain a reaction mixture; the reaction mixture was stirred at room temperature for 2 to 6 hours, then cooled to -5 to 5°C, and finally compound M3 was added. After the addition was completed, the reaction mixture was stirred at room temperature for 18 to 24 hours to obtain a reaction solution. The reaction solution was quenched with water, then extracted with an organic solvent. The extracted organic phase was collected, dried, filtered, and the filtrate was collected and evaporated under reduced pressure to obtain a crude product. The crude product was purified to obtain an oily substance. An aromatic hydrocarbon organic solvent was added to the oily substance and evaporated under reduced pressure to obtain compound M4. S5: First, mix 1% Grubbs2 catalyst with anhydrous dichloromethane, then add M4 compound, and stir the mixture at room temperature under a nitrogen atmosphere for 16-24 hours to obtain a reaction solution containing M5 compound. The reaction solution can be used directly in the next reaction step; or the reaction solution can be evaporated under reduced pressure to obtain a crude product, which can then be purified to obtain compound M5. S6: First, mix the reaction solution containing compound M5 or compound M5 with dichloromethane, then add manganese dioxide to obtain a mixture; stir the mixture at room temperature for 16-24 hours to obtain a reaction solution; filter the reaction solution, collect the filtrate and evaporate it under reduced pressure to obtain a crude product; pulp the crude product to obtain the target product.
2. The method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one according to claim 1, characterized in that, In step S1, the acid is p-toluenesulfonic acid monohydrate; step S1 is as follows: Under nitrogen protection, D-ribose and acetone were mixed to obtain a mixture; the temperature of the mixture was adjusted to the range of 0-10℃, and then p-toluenesulfonic acid monohydrate and 2,2-dimethoxypropane were added. The mixture was stirred at room temperature for 2.5-6 hours to obtain a reaction solution; the pH of the reaction solution was adjusted to 7-8, filtered, and the filtrate was collected and evaporated under reduced pressure to obtain compound M1.
3. The method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one according to claim 2, characterized in that, The molar ratio of D-ribose, p-toluenesulfonic acid monohydrate, and 2,2-dimethoxypropane is 1:(0.01–0.2):(0.9–1.2).
4. The method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]dioxacyclopenten-4(6aH)-one according to claim 1, characterized in that, In step S1, the acid is sulfuric acid; step S1 is as follows: Under nitrogen protection, D-ribose and acetone were mixed to obtain a mixture; sulfuric acid was added to the mixture, and the mixture was stirred at room temperature for 3-8 hours to obtain a reaction solution; the pH of the reaction solution was adjusted to 7-8, filtered, and the filtrate was collected and evaporated under reduced pressure to obtain compound M1.
5. The method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one according to claim 1, characterized in that, The S2 step is as follows: Under nitrogen protection, compound M1 and anhydrous tetrahydrofuran were mixed to obtain a mixture; the temperature of the mixture was adjusted to -30 to -10 °C, and then Grignard reagent was added dropwise to obtain a reaction mixture; the reaction mixture was reacted at -5 to 5 °C for 16 to 24 h to obtain a reaction solution; water was added to the reaction solution, and then extracted with an organic solvent. The organic phase was collected and evaporated under reduced pressure to obtain compound M2.
6. The method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one according to claim 1, characterized in that, The S2 step is as follows: Under nitrogen protection, compound M1 and anhydrous tetrahydrofuran were mixed to obtain a mixture; the temperature of the mixture was adjusted to -20 to 25°C, and then Grignard reagent was added dropwise to obtain a reaction mixture; the reaction mixture was reacted at room temperature for 16 to 24 hours to obtain a reaction solution; the reaction solution was added to ice, and the supernatant was evaporated under reduced pressure to obtain compound M2.
7. The method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]dioxacyclopenten-4(6aH)-one according to claim 5 or 6, characterized in that, In step S2, the molar ratio of compound M1 to Grignard reagent is 1:(2.5-4).
8. The method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadieno[d][1,3]dioxacyclopenten-4(6aH)-one according to claim 5 or 6, characterized in that, In step S2, the Grignard reagent is vinyl magnesium bromide.
9. The method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one according to claim 1, characterized in that, In step S4, the aromatic hydrocarbon organic solvent is toluene.
10. The method for synthesizing (3aR,6aR)-2,2-dimethyltetrahydro-3aH-cyclopentadien[d][1,3]dioxacyclopenten-4(6aH)-one according to claim 1, characterized in that, In step S5, the ratio of M4 compound to dichloromethane is 1 g:(25-50) mL.