Preparation method of oseltamivir intermediate
Patent Information
- Application Number
- CN202380083369.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Priority Date
- 2022-12-15
- Filing Date
- 2023-12-14
- Publication Date
- 2025-07-11
AI Technical Summary
The existing oseltamivir synthesis route uses highly toxic substances such as sodium azide, which involves explosion risks and high production costs. The post-processing is complex and there is a lack of efficient and green preparation methods.
Trichloroacetic acid, formic acid, acetic acid, etc. are used as de-tert-butyl reagents under acidic conditions to replace trifluoroacetic acid, and are combined with hydrocarbon or aromatic hydrocarbon solvents for reaction and post-processing to reduce the generation of hydrolysis impurities and simplify purification steps.
It reduces production costs, improves molecule utilization, simplifies post-processing steps, is suitable for large-scale commercial production, and reduces the risk of equipment corrosion and heavy metal excess.
Abstract
Description
A preparation method of oseltamivir intermediate Technical Field
[0001] The present invention belongs to the field of chemical synthesis, and in particular relates to a method for preparing an oseltamivir intermediate. Background Art
[0002] Oseltamivir phosphate is an anti-influenza drug that acts as a specific inhibitor of neuraminidase. It can inhibit mature influenza viruses from leaving host cells, thereby inhibiting the spread of influenza viruses in the human body to treat influenza. It is considered to be an effective and highly specific influenza treatment drug.
[0003] The chemical name of oseltamivir phosphate is (3R,4R,5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate (1:1), and its structure is shown in the following formula:
[0004] Currently, there are many synthetic routes for oseltamivir phosphate, which are mainly divided into azide synthetic routes and non-azide synthetic routes. Given that the azide route requires highly toxic substances such as sodium azide, azide is highly explosive, and production safety pressures are high, the synthetic route disclosed in CN100545145C is commonly used in industry. This route mainly includes oxygen ring opening, nitrogen ring synthesis, nitrogen ring opening, acylation, salt formation, de-tert-butylation, de-diallylation, and then phosphate formation. The reaction formula is as follows:
[0005] This route is a relatively practical scheme with a high yield. Trifluoroacetic acid is used in the de-tert-butylation. On the one hand, trifluoroacetic acid acts as a strong acid to catalyze the de-tert-butylation, and on the other hand, it is used as a solvent, so the amount of trifluoroacetic acid used is relatively large. In addition, the treatment after the reaction is relatively complicated. The trifluoroacetic acid is first evaporated under vacuum, and then toluene-hexane (1:1) is added and concentrated in vacuo. The residual oil is diluted with toluene-hexane (1:1), and saturated sodium carbonate solution is added. The mixture is stirred for 15 minutes, and water is added to separate the layers. The aqueous layer is extracted with toluene-hexane. The aqueous layer is diluted with toluene, and an aqueous sodium hydroxide solution is added to adjust the pH to 13-14. The layers are separated, the aqueous layer is extracted, the organic layers are combined, and concentrated in vacuo to obtain a brown slurry. The purity and yield are not disclosed.
[0006] CN109438276A discloses a method for synthesizing an oseltamivir intermediate compound 2, wherein trifluoroacetic acid is used for de-tert-butylation, the reaction solvent is toluene, and the reaction is stirred at 45-55°C. After the reaction is completed, toluene is added, the temperature is lowered to 0-10°C, and then cold water is added. An aqueous sodium hydroxide solution is slowly added dropwise to adjust the pH to about 12-13, extraction is performed, filtration is performed, and the filtrate is concentrated under reduced pressure in a hot water bath, and then n-heptane is added and stirred for 2 hours, crystallized, and dried.
[0007] CN111253276B uses the same method to remove the tert-butyl group, wherein the amount of trifluoroacetic acid used is 4 times that of the oseltamivir intermediate compound 1. After the reaction, toluene and water are added, the temperature is controlled at 10°C, and the pH is adjusted to 9 with 10% sodium carbonate solution. The aqueous layer is extracted with toluene three times, and the combined organic layers are washed with water until neutral, dried over anhydrous sodium sulfate, and concentrated under reduced pressure at 60°C to obtain an oil with a yield of 96.2% and a content of 97.3%.
[0008] CN109438276A discloses a method for synthesizing oseltamivir, wherein acetonitrile is used as a solution and concentrated sulfuric acid is added as a catalyst during the de-tert-butylation reaction.
[0009] According to the Newport database query, the API usage of oseltamivir phosphate in 2021 was close to 20 tons. The API usage of this product is large, so it is very necessary to develop a cost-effective, efficient and green preparation method.
[0010] Summary of the Invention
[0011] In response to the shortcomings and deficiencies in the prior art, the present invention provides a method for preparing an oseltamivir intermediate, which replaces the original expensive reagents with lower-cost materials, uses less dosage, improves molecular utilization, greatly reduces costs, and simplifies post-processing, making it very suitable for large-scale commercial production.
[0012] The present invention provides a method for preparing an oseltamivir intermediate as shown in Formula 2, which comprises the following steps:
[0013] The compound of formula 1 is subjected to a de-tert-butylation reaction under acidic conditions to obtain a compound of formula 2;
[0014] The acidic conditions are trichloroacetic acid, chloroacetic acid, dichloroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, formic acid or a mixture thereof.
[0015] In some embodiments, the de-tert-butylation reaction temperature is 40 to 100° C., preferably 50 to 85° C.; the reaction time is 10 to 48 hours, preferably 5 to 14 hours.
[0016] In some embodiments, the mass ratio of the compound of Formula 1 to the acid is 1:0.7-5, and the preferred mass ratio is 1:0.8-2.0.
[0017] In some embodiments, the acidic condition is formic acid, acetic acid, methanesulfonic acid or a mixture thereof; when a mixture is used, preferably a mixture of acetic acid and methanesulfonic acid, or a mixture of formic acid and methanesulfonic acid; wherein the molar ratio of methanesulfonic acid to acetic acid or formic acid is 1:15-25.
[0018] In some embodiments, the obtained compound of formula 2 further includes the following post-processing steps: after the reaction is completed, it is dissolved in an organic solvent to obtain a solution containing the compound of formula 2, and then the solution of the compound of formula 2 obtained above is cooled and the pH value is adjusted to 7 to 14 (for example, 7 to 8, 8 to 10 or any value or range therebetween) with an inorganic base aqueous solution, extracted and separated, and concentrated to obtain the compound.
[0019] In some embodiments, after the reaction is completed, the feed solution can be concentrated under reduced pressure, then cooled to room temperature and dissolved in an organic solvent to obtain a solution containing the compound of formula 2.
[0020] In some embodiments, the organic solvent is a halogenated hydrocarbon solvent or an aromatic hydrocarbon solvent, and its amount is 5 to 10 volume equivalents of the reaction solution.
[0021] In some embodiments, the halogenated hydrocarbon solvent is dichloromethane or dichloroethane, and the aromatic hydrocarbon solvent is selected from toluene.
[0022] In some embodiments, the temperature for cooling and adjusting the pH of the solution of the compound of Formula 2 is -10 to 10°C, such as 0 to 10°C, -10 to 5°C, or any value or range therebetween.
[0023] In some embodiments, the inorganic base aqueous solution is selected from a saturated sodium bicarbonate aqueous solution and a sodium hydroxide aqueous solvent; wherein the mass percentage concentration of the aqueous solution is 8-10%, preferably 10-15%.
[0024] To date, the prior art does not disclose the use of trichloroacetic acid, formic acid, acetic acid, or the like as acidic solvents for the de-tert-butylation reaction. Trifluoroacetic acid is used in large quantities and is expensive. The inventors unexpectedly discovered that the use of trichloroacetic acid, formic acid, acetic acid, methanesulfonic acid, or mixtures thereof as acidic solvents can achieve the same effect while significantly reducing costs.
[0025] In addition, the inventors repeated the method disclosed in CN109438276A and found that serious carbonization occurred after adding concentrated sulfuric acid. In addition, the process used expensive solvent acetonitrile, resulting in high overall costs.
[0026] The inventors have found that adding the reaction solution to a hydrocarbon solvent or an aromatic hydrocarbon solvent has a good dissolution effect, and no water is needed to dissolve it. In the post-treatment step, the reaction solution is added dropwise to a saturated sodium bicarbonate aqueous solution. At this time, the reaction solution is always in a weak alkaline or neutral state, and the hydrolysis impurities produced are relatively small, and subsequent multiple extraction and recrystallization purification are not required. The structural formula of the hydrolysis impurity is:
[0027] When the pH value of the reaction solution is adjusted with an aqueous sodium hydroxide solution, a small amount of hydrolysis product will be produced, which can be removed by washing with water in post-treatment. The yield and product quality level are equivalent to those using sodium bicarbonate.
[0028] Compared with the prior art, the present invention has the following positive technical effects:
[0029] 1. The preparation method provided by the present invention uses weak acids such as formic acid and acetic acid instead of trifluoroacetic acid, which improves molecular utilization, has obvious cost advantages, avoids damage to equipment caused by the strong corrosiveness of strong acids, and reduces the risk of excessive heavy metals in the product.
[0030] 2. The preparation method provided by the present invention uses a hydrocarbon or aromatic hydrocarbon solvent for post-treatment, which has a good dissolving effect and does not require the addition of water to assist dissolution.
[0031] 3. The preparation method provided by the present invention has high reaction efficiency, simple purification system, easy solvent recovery, is green and environmentally friendly, and is suitable for large-scale industrial production. DETAILED DESCRIPTION
[0032] The following examples are used only to illustrate the present invention, but are not intended to limit the scope of the present invention.
[0033] Example 1:
[0034] 80 kg of formic acid was added to a four-necked flask, the temperature was raised to 75°C, and stirring was started. 40 kg of compound 1 was added in batches to the four-necked flask containing formic acid, and the temperature was maintained at 75°C for 12 hours with stirring. The HPLC control showed that compound 1 was ≤ 0.5%. After the reaction was completed, the reaction solution was controlled at 75°C and concentrated to dryness under reduced pressure. The feed liquid was cooled to room temperature and 200 L of dichloromethane was added and stirred to dissolve. The temperature was slowly lowered to 0-10°C, and the feed liquid was maintained at 0-10°C. The feed liquid was slowly added to about 60 kg of supersaturated sodium bicarbonate aqueous solution. The pH value showed 7-8, and then the layers were separated. The aqueous layer was extracted once with 100 L of dichloromethane. The two organic layers were combined and concentrated under reduced pressure to constant weight to obtain a yellow to white solid compound 2 with a yield of about 96% and a purity of 98.8%, of which the hydrolyzed impurities were 0.25%.
[0035] Example 2:
[0036] 90 kg of trichloroacetic acid was added to a four-necked flask, the temperature was raised to 75°C, and stirring was started. 40 kg of compound 1 was added in batches to the four-necked flask containing trichloroacetic acid, and the temperature was maintained at 75°C for 14 hours. The reaction was controlled by HPLC, and the concentration of compound 1 was ≤ 0.5%. After the reaction was completed, the feed liquid was cooled to room temperature and then 200 L of dichloroethane was added and stirred to dissolve. The temperature was slowly lowered to 0-10°C, and the feed liquid was maintained at 0-10°C. The feed liquid was slowly added to about 60 kg of supersaturated sodium carbonate aqueous solution. The pH value showed 7-8. The layers were then separated, and the aqueous layer was extracted once with 100 L of dichloroethane. The two organic layers were combined and concentrated under reduced pressure to constant weight to obtain a yellow to white solid compound 2 with a yield of about 92% and a purity of 97.5%.
[0037] Example 3:
[0038] 80 kg of acetic acid was added to a four-necked flask and heated to 75°C. Stirring was started, 40 kg of compound 1 was added in batches to the four-necked flask containing acetic acid, and the temperature was maintained at 85°C for 14 hours with stirring. The HPLC control showed that compound 1 was ≤0.5%. The mixture was concentrated under reduced pressure at 75°C to dryness. After the liquid was cooled to room temperature, 200 L of dichloroethane was added and stirred to dissolve. The temperature was slowly lowered to 0-10°C, and the liquid was maintained at 0-10°C. The liquid was slowly added to about 60 kg of a supersaturated sodium bicarbonate aqueous solution. The pH value showed 7-8. The layers were separated, and the aqueous layer was extracted once with 100 L of dichloroethane. The two organic layers were combined and concentrated under reduced pressure to constant weight to obtain a yellow to white solid compound 2 with a yield of about 94.5% and a purity of 98.2%.
[0039] Example 4:
[0040] 70 kg of formic acid was added to the reactor and stirring was started. 40 kg of compound 1 was added to the reactor containing formic acid in batches and maintained at 65-75 ° C. The reaction was stirred for 7-12 hours. The HPLC control showed that compound 1 was ≤ 0.5%. After the feed liquid was cooled to room temperature, 200 L of toluene was added and stirred to dissolve. The temperature was slowly lowered to -10-5 ° C. The feed liquid was maintained at -10-5 ° C. and was slowly added to about 420 kg of 15% sodium hydroxide aqueous solution. The pH value showed 8-10. The layers were separated and the aqueous layer was extracted once with 100 L of toluene. The two organic layers were combined and washed once with 50 L of drinking water. The organic layer was concentrated under reduced pressure to constant weight to obtain a yellow to white solid compound 2 with a yield of about 94.7% and a purity of 98.1%.
[0041] Example 5:
[0042] 34 kg of formic acid was added to the reactor, stirring was started, the temperature was lowered to 20-30 ° C, and about 5 kg of methanesulfonic acid was slowly added dropwise. After the addition was completed, stirring was continued for 20-30 minutes. 40 kg of compound 1 was added in batches to a reactor containing a mixture of formic acid and methanesulfonic acid, and the mixture was kept at 50-60 ° C and stirred for 5-8 hours. The HPLC control showed that compound 1 was ≤ 0.5%. After the feed solution was cooled to room temperature, 200 L of toluene was added and stirred to dissolve. The temperature was slowly lowered to -10-5 ° C, the feed solution was maintained at -10-5 ° C, and about 220 kg of 15% sodium hydroxide aqueous solution was slowly added. The pH value showed 8-10. After separation, the aqueous layer was extracted once with 100 L of toluene. The two organic layers were combined and washed once with 50 L of drinking water. The organic layer was concentrated under reduced pressure to constant weight to obtain a yellow to white solid compound 2 with a yield of about 95.0% and a purity of 98.5%, of which the hydrolyzed impurities were 0.28%.
[0043] Comparative Example 1: (Refer to CN100545145C)
[0044] 311 g of trifluoroacetic acid was added to a four-necked flask, cooled to 0-5°C, stirred, and then added to 42.56 g of compound 1. The temperature was maintained at 25°C, and the reaction was stirred for 5.5 hours. The HPLC control showed that compound 1 was ≤ 0.5%. After the reaction was completed, the reaction solution was concentrated to dryness under reduced pressure at 30°C. The feed solution was cooled to room temperature and 150 ml of toluene:hexane = 1:1 (v:v) was added and stirred for dilution. The temperature was slowly lowered to 0-10°C, the feed solution was maintained at 0-10°C, and about 150 ml of saturated sodium carbonate was slowly added. Then 150 ml of water was added, and the layers were separated. The aqueous layer was extracted with 50 ml of toluene:hexane = 1:1 (v:v). The reaction mixture was stirred for 2 hours, and the organic layers were combined and extracted twice with 2N hydrochloric acid (30 ml for the first time and 15 ml for the second time). The combined aqueous layers were diluted with 100 ml of toluene, and then 5.67 g (142 mmol) of sodium hydroxide was dissolved in 17 ml of water to obtain a pH of 13-14. The layers were separated, and the aqueous layer was extracted three times with 50 ml of toluene. The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to a constant weight to obtain 38.73 g of a brown oil. 200 ml of hexane was added, and seed crystals were added. The mixture was stirred at 25 ° C for about 24 hours, and a large amount of solid was precipitated, about 26.76 g, with a yield of 72% and a purity of about 98.0%.
[0045] Table 1 is a comparison of the results of Examples 1 to 3 and Comparative Example 1 *Note: The price of formic acid is about 8 yuan / kg, and the price of trifluoroacetic acid is about 72 yuan / kg.
[0046] As can be seen from the results in Table 1 above, the technical solution of the present invention has a cost advantage. When cheaper reagents are used to replace expensive reagents for the reaction, the reaction yield is not affected and the yield is improved to a certain extent, which is very suitable for large-scale industrial production.
[0047] The specific embodiments described herein are merely illustrative of the spirit of the present invention. Persons skilled in the art may make various modifications, additions, or substitutions to the described specific embodiments without departing from the spirit of the present invention or exceeding the scope of the appended claims.
Claims
1. A method for preparing an oseltamivir intermediate as shown in Formula 2, characterized in that: The method comprises the following steps: subjecting the compound of formula 1 to a de-tert-butylation reaction under acidic conditions to obtain a compound of formula 2; The acidic conditions are trichloroacetic acid, chloroacetic acid, dichloroacetic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, formic acid or a mixture thereof.
2. The preparation method according to claim 1, characterized in that The de-tert-butylation reaction temperature is 40-100° C., preferably 50-85° C.; the reaction time is 3-48 hours, preferably 5-14 hours.
3. The preparation method according to claim 1, characterized in that The mass ratio of the compound of formula 1 to the acid is 1:0.7-5, and the preferred mass ratio is 1:0.8-2.
0.
4. [Corrected 22.12.2023 according to Rule 26] The preparation method according to claim 1, characterized in that The acidic conditions are acetic acid, formic acid, methanesulfonic acid or a mixture thereof.
5. The preparation method according to claim 1, characterized in that The method further comprises the following post-processing step: after the reaction is completed, dissolving the compound of formula 2 with an organic solvent to obtain a solution, cooling the solution of the compound of formula 2 obtained above, adjusting the pH value with an inorganic alkali aqueous solution, extracting and separating the layers, and concentrating the solution to obtain the compound.
6. The preparation method according to claim 5, characterized in that After the reaction is completed, the feed liquid can be concentrated under reduced pressure, then cooled to room temperature and dissolved in an organic solvent to obtain a solution containing the compound of formula 2.
7. The preparation method according to claim 5, characterized in that The organic solvent is a halogenated hydrocarbon solvent or an aromatic hydrocarbon solvent, and its usage is 5 to 10 volume equivalents of the reaction solution.
7. The preparation method according to claim 5, characterized in that the pH value is 7 to 14.
8. The preparation method according to claim 5, characterized in that The halogenated hydrocarbon solvent is selected from dichloromethane or dichloroethane, and the aromatic hydrocarbon is selected from toluene.
9. The preparation method according to claim 5, characterized in that The temperature for cooling and adjusting pH value is -10 to 10°C.
10. The preparation method according to claim 5, characterized in that The inorganic alkali aqueous solution is selected from saturated sodium bicarbonate aqueous solution and sodium hydroxide aqueous solvent; wherein the mass percentage concentration of the aqueous solution is 8-10%, preferably 10-15%.
11. The preparation method according to claim 4, characterized in that The acidic conditions are acetic acid, formic acid, a mixture of acetic acid and methanesulfonic acid, or a mixture of formic acid and methanesulfonic acid; when a mixture is used, the molar ratio of methanesulfonic acid to acetic acid or formic acid is 1:15-25.