A method for preparing oseltamivir methyl ester

Abstract

The application relates to the technical field of organic synthesis, and provides a preparation method of oseltamivir methyl ester, which comprises the following steps: reacting a compound shown in formula A in a solvent in the presence of zinc powder and ammonium chloride, adding an ethanol solution of phosphoric acid after the reaction is completed, and obtaining the oseltamivir methyl ester, wherein the molar ratio of the compound shown in formula A to the zinc powder is 1:4-6. The application provides a synthesis route which is easy to obtain raw materials, has mild reaction conditions, is easy to control operation, and is safe and reliable.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing methyl oseltamivir. Background Technology

[0002] Oseltamivir is a highly selective neuraminidase inhibitor compound used for the treatment and prevention of influenza virus infection, bronchitis with accompanying infections, pneumonia, general pain, and severe fever. Oseltamivir capsules were approved in China in 2001, marketed as Tamiflu, with a strength of 75mg. It is one of the most effective drugs against both H1N1 and influenza B viruses.

[0003] Oseltamivir compounds have three chiral centers and seven opposing chiral isomers. These compounds have similar properties and produce similar impurity structures, which can have a significant impact on the quality and stability of the product.

[0004] CN108047077A discloses a method for preparing a chiral impurity of oseltamivir, which uses sodium azide to attack an epoxide derivative from the back. CN106278928A discloses a method for synthesizing an isomer impurity of oseltamivir phosphate, in which the final step uses a 10% palladium on carbon, Raney nickel, and 5% platinum on carbon catalyst to remove the amino protecting group via hydrogenolysis and form a phosphate, which is then purified to obtain the target compound. CN115490591A discloses a novel intermediate impurity compound of oseltamivir phosphate, which can be used as a standard for oseltamivir phosphate toxic impurities, and can help improve the quality control of oseltamivir phosphate raw material.

[0005] The aforementioned method discloses the use of epoxide compounds as core intermediates in the synthesis of oseltamivir impurities. However, during the synthesis, a very small portion of oseltamivir methyl ester compounds undergoes exchange, generating impurities that are extremely difficult to separate and may ultimately affect the purity of oseltamivir. Furthermore, oseltamivir methyl ester is also a precursor form of neuraminidase inhibitors and antiviral oseltamivir acid. It can be converted to oseltamivir acid via carboxylesterase 1 (CES1). Therefore, the synthesis of oseltamivir methyl ester is of significant importance, yet very little research has been conducted on its synthesis.

[0006] Therefore, the development of a synthetic route for oseltamivir methyl ester is of great significance for the quality control and analytical testing of oseltamivir. Summary of the Invention

[0007] The technical problem to be solved by the present invention is that there is no method for preparing methyl oseltamivir in the prior art.

[0008] To solve the above-mentioned technical problems, the present invention provides a method for preparing methyl oseltamivir, wherein the preparation method is as follows: the compound shown in formula A is reacted in a solvent in the presence of zinc powder and ammonium chloride, and after the reaction is completed, a phosphoric acid ethanol solution is added to obtain the methyl oseltamivir, wherein the molar ratio of the compound shown in formula A to zinc powder is 1:4 to 6.

[0009]

[0010] Preferably, the molar ratio of compound A to ammonium chloride is 1:4 to 6, for example, it can be 1:4, 1:5, 1:6, etc.

[0011] Preferably, the solvent is a mixture of ethanol and water.

[0012] Preferably, the reaction temperature is 20-30°C, for example, it can be 20°C, 24°C, 28°C or 30°C.

[0013] Preferably, the reaction time is 4 to 6 hours, for example, 4 hours, 5 hours, 6 hours, etc.

[0014] Preferably, the mass concentration of the phosphate ethanol solution is 83% to 85%, for example, it can be 83%, 84% or 85%.

[0015] In this invention, the designed route uses quinolinic acid as the starting material and proceeds through 12 steps to obtain the target product. However, the preparation of aziridine from trimethylphosphine requires extremely high moisture content, which is difficult to control in industrial production. Furthermore, trimethylphosphine is a highly flammable and explosive substance. The hydrogenation reduction of the azide group using Lindlar and Raney nickel as catalysts to prepare the free base of oseltamivir phosphate requires a long reaction time, resulting in a long production cycle and safety hazards due to prolonged hydrogen gas flow. Another route, using shikimic acid as the starting material, first methylates it, then modifies its structure through a series of reactions, converts the methyl ester to an ethyl ester, and finally reduces the azide group to obtain oseltamivir, involving 16 steps. This route is lengthy and has a low overall yield. In addition, most current methods use tributylphosphine or triphenylphosphine to reduce the azide group, resulting in products with high impurity content. Therefore, to address the aforementioned issues, this design route utilizes commercially available raw materials through a high-yield hydrolysis reaction and a one-step acidic methyl esterification reaction, simultaneously deprotecting to obtain a high-yield converted hydrochloride key intermediate. Subsequently, it is reduced by compound A to finally prepare oseltamivir methyl ester. This step has a high yield, uses zinc powder reduction, has mild reaction conditions, is easy to operate, reduces the risk of safety hazards, and avoids the problem of difficult separation of related impurities generated during other preparation methods.

[0016] In this invention, after the zinc powder reduction reaction is completed, a phosphoric acid ethanol solution is used to crystallize and obtain a crude product. Generally, a phosphoric acid ethanol solution is added to the product of the reduction reaction at 20-30°C, and after crystallization, the product is filtered and dried to obtain a crude product. The crude product is then dissolved in acetone and water, activated carbon is added, filtered, and further crystallized and dried to obtain a pure product.

[0017] Preferably, the compound of formula A is prepared by reacting the compound of formula B with acetic anhydride in a solvent in the presence of a base;

[0018]

[0019] In this reaction step, acetic anhydride is used to form amide bonds with amino groups, while ensuring the presence of azides and not affecting the methyl ester groups, thus laying the foundation for subsequent reduction.

[0020] Preferably, the molar ratio of compound B to acetic anhydride is 1:1 to 1.5, for example, it can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 or 1:1.5, etc.

[0021] Preferably, the base is triethylamine.

[0022] Preferably, the solvent is dichloromethane and / or trichloromethane.

[0023] Preferably, the reaction temperature is -5℃ to 10℃, for example, it can be -5℃, -2℃, 0℃, 3℃, 5℃, 8℃ or 10℃, etc.

[0024] Preferably, the reaction time is 0.5 to 2 hours, for example, 0.5 hours, 1 hour, 1.5 hours or 2 hours.

[0025] Preferably, the compound of formula B is prepared by reacting the compound of formula C with azidetrimethylsilane in a solvent in the presence of ammonium chloride and triethylamine;

[0026]

[0027] In this reaction, the product is obtained by extraction with ethyl acetate, followed by drying and removal of the solvent after the reaction is complete.

[0028] Preferably, the molar ratio of the compound of formula C to azidetrimethylsilane, ammonium chloride, and triethylamine is 1:1.5-2:1.5-2:0.4-0.6, for example, it can be 1:1.5:1.5:0.5, 1:1.6:1.7:0.6, etc.

[0029] Preferably, the solvent is N,N-dimethylformamide;

[0030] Preferably, the reaction temperature is 50-60°C, for example, 50°C, 55°C, or 60°C.

[0031] Preferably, the reaction time is 10 to 18 hours, for example, it can be 10 hours, 12°C, 15°C or 18 hours.

[0032] Preferably, the compound of formula C is prepared by the following process: the compound of formula E is hydrolyzed with lithium hydroxide in a solvent to obtain the compound of formula D, and then the compound of formula D is deprotected and esterified with thionyl chloride to obtain the compound of formula C;

[0033]

[0034] The reaction process, through reduction and further ring closure, is easy to operate and directly forms a chiral closed-loop three-membered ring.

[0035] Preferably, the molar ratio of the compound of formula E to lithium hydroxide is 1:0.4 to 0.6, for example, it can be 1:0.4, 1:0.5 or 1:0.6.

[0036] Preferably, the solvent in the hydrolysis reaction is a mixed solution of methanol and water with a volume ratio of 10:1.

[0037] Preferably, the temperature of the hydrolysis reaction is 40 to 60°C, for example, 40°C, 45°C, 50°C, 55°C or 60°C.

[0038] Preferably, the hydrolysis reaction takes 10 to 15 hours, for example, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, or 15 hours.

[0039] Preferably, the molar ratio of the compound of formula D to thionyl chloride is 1:0.4 to 0.8, for example, it can be 1:0.4, 1:0.5, 1:0.6, 1:0.7 or 1:0.8.

[0040] Preferably, the solvent for the deprotection esterification reaction is methanol.

[0041] Preferably, the preparation process of compound E is as follows: compound G and triphenylmethylamine are reacted in toluene in the presence of magnesium chloride to obtain compound F, and then compound F is reacted with methanesulfonyl chloride in toluene in the presence of triethylamine hydrochloride to obtain compound E.

[0042] In the reaction process for preparing formula F, the reaction temperature is generally controlled at 50-60℃, and the reaction is carried out overnight for about 20 hours. After the reaction is completed, the temperature is lowered and the pH is adjusted to 8 with citric acid. The product is obtained by extraction with toluene and concentration by separation. The product is further dissolved in toluene and then washed with hydrochloric acid, sodium bicarbonate and water in sequence to remove the solvent and obtain the product compound F.

[0043] In the process of preparing compound E from compound F, the reaction temperature is controlled at 50-60℃. After the reaction is completed, the product compound E is obtained by extraction with ethyl acetate, separation, and removal of solvent.

[0044] Preferably, the molar ratio of the compound of formula G to triphenylmethylamine and magnesium chloride is 1:1 to 1.5:0.8 to 1, for example, it can be 1:1.2:0.8, 1:1.4:1, etc.

[0045] Preferably, the molar ratio of the compound of formula F to methanesulfonyl chloride and triethylamine hydrochloride is 1:1.1 to 1.5:1.5 to 2.5, for example, it can be 1:1.1:1.5, 1:1.2:1.8, 1:1.5:2, etc.

[0046]

[0047] As a preferred technical solution, the present invention provides a method for preparing oseltamivir methyl ester, the preparation method comprising the following steps:

[0048] (1) Compound G and triphenylmethylamine were reacted in toluene at 50-60°C for 20-25 h in the presence of magnesium chloride, with the molar ratio of compound G to triphenylmethylamine and magnesium chloride being 1:1-1.5:0.8-1, to obtain compound F. Then, compound F and methanesulfonyl chloride were reacted in toluene at 50-60°C for 6-10 h in the presence of triethylamine hydrochloride, with the molar ratio of compound F to methanesulfonyl chloride and triethylamine hydrochloride being 1:1.1-1.5:1.5-2.5, to obtain compound E.

[0049]

[0050] (2) Compound E is hydrolyzed with lithium hydroxide in a mixed solution of methanol and water at a volume ratio of 10:1 at 40-60°C for 10-15 h to obtain compound D. The molar ratio of compound E to lithium hydroxide is 1:0.4-0.6. Then, compound D is deprotected and esterified with thionyl chloride in methanol at a molar ratio of 1:0.4-0.8 to obtain compound C.

[0051]

[0052] (3) Compound C was reacted with azidotrimethylsilane in N,N-dimethylformamide at 50-60°C for 10-18 h in the presence of ammonium chloride and triethylamine to prepare compound B. The molar ratio of compound C to azidotrimethylsilane, ammonium chloride and triethylamine was 1:1.5-2:1.5-2:0.4-0.6.

[0053]

[0054] (4) Compound B of formula B with acetic anhydride in a molar ratio of 1:1 to 1.5 was reacted with triethylamine in dichloromethane and / or trichloromethane at -5°C to 10°C for 0.5 to 2 h to prepare compound A;

[0055]

[0056] (5) The compound shown in Formula A is reacted in a mixed solution of ethanol and water in the presence of zinc powder and ammonium chloride at 20-30°C for 4-6 hours. After the reaction is completed, a phosphoric acid ethanol solution with a mass concentration of 83%-85% is added to obtain the methyl oseltamivir. The molar ratio of the compound shown in Formula A to zinc powder is 1:4-6; the molar ratio of the compound in Formula A to ammonium chloride is 1:4-6.

[0057]

[0058] Implementing this invention has the following beneficial effects:

[0059] This invention provides a synthetic route that features readily available reactants, mild reaction conditions, easy operation control, and safety and reliability. Starting with a commercially available epoxy intermediate (SM), the route involves ring-opening with triphenylmethylamine epoxy resin, chiral ring-closure, hydrolysis, and esterification, followed by reduction to obtain methyl oseltamivir. The overall route is short, yields high, and is easy to operate. The product is of significant importance for quality control in the oseltamivir production process. Attached Figure Description

[0060] Figure 1 The image shows the hydrogen nuclear magnetic resonance spectrum of methyl oseltamivir, the product prepared in the example. Detailed Implementation

[0061] The following provides a detailed description of specific embodiments of the present invention. It should be understood that the specific embodiments described herein are for illustrative and explanatory purposes only and are not intended to limit the scope of the invention.

[0062] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0063] Example 1

[0064] This embodiment provides a method for preparing oseltamivir methyl ester. (1)

[0066]

[0067] Under nitrogen protection, anhydrous magnesium chloride (3.4 g, 0.036 mol), toluene (30 mL), and triphenylmethylamine (14.0 g, 0.054 mol) were added to a 100 mL reaction flask with mechanical stirring, a thermometer, and a reflux condenser. The reaction was continued for 6 h at a temperature below 25 °C. Compound G (oseltamivir impurity) (10.2 g, 0.04 mol) and toluene (30 mL) were added to a 50 mL reaction flask and stirred for 1 h until the solid was completely dissolved. The toluene solution of compound G was added to the aforementioned 100 mL reaction flask. Under nitrogen protection, the temperature was raised and maintained at 55 °C for 20 h overnight.

[0068] The solution was cooled to 4°C in a water bath, and the pH was adjusted to 8 with 10% citric acid. The aqueous phase was separated, and extracted twice with toluene (30 ml). The organic phases were combined and washed with water (30 ml). The organic phase was concentrated to dryness to give 13.6 g of an oil.

[0069] Add the above oily substance (13.6 g) and toluene (60 ml) to a 250 mL reaction flask and start stirring. Wash with 6 M hydrochloric acid solution (30 ml). Wash the organic phase once with 1 M sodium bicarbonate solution (30 ml), and then once with water (30 ml). Concentrate the organic phase under reduced pressure to dryness to give 14.0 g of a pale yellow oily compound of formula F. Yield: 68%. Purity: 97.8%.

[0070] To the obtained oily compound F (14.0 g, 0.027 mol), 120 mL of toluene was added, and the mixture was stirred to dissolve. The temperature was controlled below 50 °C. Methanesulfonyl chloride (4.6 g, 0.04 mol) and triethylamine hydrochloride (7.4 g, 0.054 mol) were added, and the mixture was heated to 55 °C and reacted for 8 h. Thin-layer chromatography was used to determine the endpoint as the intermediate reaction was complete. The reaction mixture was cooled to 25 °C, filtered, and the filtrate was transferred to a separatory funnel. 150 mL of ethyl acetate and 250 mL of saturated brine were added to separate the layers. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure (≥0.08 MPa) at 90 °C to obtain a brownish-red oily compound E, 11.9 g, yield 88%. (2)

[0072]

[0073] Using methanol and water in a volume ratio of 10:1, 11.9 g (0.024 mol) of the brownish-red oily compound E obtained in the previous step was added to a solution containing 2.88 g (0.12 mol) of lithium hydroxide hydrolysate. The mixture was stirred to dissolve, heated to 50 °C, and reacted overnight. 11 g of a yellow solid, compound D, was obtained, with a yield of 98%.

[0074] Next, using methanol as a solvent, thionyl chloride (SOCl2) (14g, 0.12mol) was added to the yellow solid compound D (11g, 0.024mol) obtained in the previous step. The reaction was exothermic, and the order and temperature of the addition were carefully controlled to prevent spillage. Simultaneously, due to the release of acidic gas, tail gas absorption was implemented. The product was concentrated using a rotary evaporator, yielding a crude oily liquid. A single molecule of HCl was bound to the basic site, and the product was purified by slurrying with anhydrous tetrahydrofuran, finally yielding compound C (4.5g), with a yield of 80%. (3)

[0076]

[0077] The product C obtained in the previous step (4.5 g, 0.019 mol) was added to a 250 mL three-necked flask, along with 35 mL of dry N,N-dimethylformamide. The mixture was stirred until dissolved, and then ammonium chloride (1.8 g, 0.034 mol), TMSN3-azidotrimethylsilane (3.7 g, 0.032 mol), and triethylamine hydrochloride (1.3 g, 0.009 mol) were added sequentially. The mixture was heated to 55 °C and reacted for 14 h. The reaction endpoint was determined by the complete reaction of compound C as detected by thin-layer chromatography. The mixture was then cooled to 25 °C, and 200 mL of water was added. The mixture was extracted with 100 mL of ethyl acetate, and the aqueous layer was discarded. The organic layer was dried over 25 g of anhydrous sodium sulfate for 1 h, filtered, and the filtrate was evaporated to dryness under reduced pressure (≥0.08 MPa) at 50 °C to obtain 4.82 g of an oily compound B (yield 91%). (4)

[0079]

[0080] The obtained oily compound of formula B was dissolved in 80 mL of dichloromethane. 2.1 g of acetic anhydride was added under stirring. The reaction mixture was cooled to 4°C, and 2.3 g of triethylamine was added dropwise at 0°C. After the addition was complete, the reaction mixture was kept at this temperature for 1 h. 200 mL of water was added to the reaction mixture, and the layers separated. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure (≥0.08 MPa) at 50°C. 50 mL of ethyl acetate and 80 mL of n-hexane were added, and the mixture was heated to 55°C and stirred for 1 h. The mixture was then cooled to 20°C to crystallize for 2 h. The crystals were filtered, and the filter cake was dried under reduced pressure (≥0.08 MPa) at 50°C for 6 h to give 5.2 g of a white solid, compound of formula A, with a yield of 92.2%. (5)

[0082]

[0083] Add 5.2 g of compound A, 100 mL of ethanol, and 35 mL of water sequentially to a 250 mL three-necked flask, stir to dissolve, then add 4.3 g of ammonium chloride and 5.24 g of zinc powder. React at 25 °C for 5 h. The reaction endpoint is reached when compound A is completely reacted as detected by thin-layer chromatography. Filter, add 100 mL of water to the filtrate, and extract with 75 mL of dichloromethane twice. Discard the aqueous layer, and evaporate the organic layer to dryness under reduced pressure (≥0.08 MPa) at 50 °C to obtain an oily substance.

[0084] Add 100 mL of ethanol to the obtained oily substance, and then add 4.9 mL of phosphoric acid (84% by mass) diluted with 45 mL of ethanol dropwise at 25 °C. Crystallize at this temperature for 1 h, filter, and dry the filter cake at 50 °C for 6 h to obtain 4.11 g of crude oseltamivir methyl ester, with a yield of 87.8%.

[0085] 4.11 g of crude oseltamivir methyl ester was added to a 250 mL dry three-necked flask, followed by 125 mL of acetone and 25 mL of water. The mixture was heated to 50 °C to dissolve the ester, and 1 g of activated carbon was added. The mixture was filtered while hot, and the filtrate was cooled to 25 ± 2 °C to crystallize for 6 h. The crystals were then filtered under vacuum and dried at 50 °C under reduced pressure for 6 h to obtain 3.5 g of pure product, with a yield of 85% and an HPLC purity of 99.80%. The 1H NMR spectrum of the product is shown below. Figure 1 As shown.

[0086] Example 2

[0087] This embodiment provides a method for preparing oseltamivir methyl ester. (1)

[0089]

[0090] Under nitrogen protection, anhydrous magnesium chloride (3.8 g, 0.039 mol), toluene (30 mL), and triphenylmethane (17.2 g, 0.066 mol) were added to a 100 mL reaction flask with mechanical stirring, a thermometer, and a reflux condenser. The reaction was continued for 8 hours at a temperature below 25°C. Compound G (oseltamivir impurity) (12.7 g, 0.05 mol) and toluene (30 mL) were added to a 50 mL reaction flask and stirred for 1.5 hours until the solid was completely dissolved. The toluene solution of compound G was added to the aforementioned 100 mL reaction flask. Under nitrogen protection, the temperature was raised and maintained at 60°C for at least 20 hours overnight.

[0091] The solution was cooled to 4°C in a water bath, and the pH was adjusted to 8 with 10% citric acid. The aqueous phase was separated, and extracted twice with toluene (30 ml). The organic phases were combined and washed with water (30 ml). The organic phase was concentrated to dryness to give 15.6 g of oil.

[0092] Add the above oily substance (13.6 g) and toluene (60 ml) to a 250 mL reaction flask and start stirring. Wash with 6 M hydrochloric acid solution (30 ml). Wash the organic phase once with 1 M sodium bicarbonate solution (30 ml), and then once with water (30 ml). Concentrate the organic phase to dryness under reduced pressure to give 16.4 g of a pale yellow oily compound of formula F. Yield: 63.5%. Purity: 97.5%.

[0093] To the obtained oily compound F (16.4 g, 0.032 mol), 120 mL of toluene was added, and the mixture was stirred to dissolve. The temperature was controlled below 50 °C. Methanesulfonyl chloride (5.7 g, 0.05 mol) and triethylamine hydrochloride (10.3 g, 0.075 mol) were added, and the mixture was heated to 65 °C and reacted for 10 h. Thin-layer chromatography was used to determine the endpoint as the intermediate reaction was complete. The reaction mixture was cooled to 22 °C, filtered, and the filtrate was transferred to a separatory funnel. 150 mL of ethyl acetate and 250 mL of saturated brine were added to separate the layers. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure (≥0.08 MPa) at 90 °C to obtain a brownish-red oily compound E, 12.7 g, yield 80%. (2)

[0095]

[0096] Using methanol and water in a volume ratio of 10:1, 12.7 g (0.026 mol) of the brownish-red oily compound E obtained in the previous step was added to a solution containing 3.1 g (0.13 mol) of lithium hydroxide hydrolysate. The mixture was stirred to dissolve, heated to 50 °C, and reacted overnight. 11.5 g of a yellow solid, compound D, was obtained, with a yield of 95%.

[0097] Next, using methanol as a solvent, thionyl chloride (SOCl2) (17.8 g, 0.15 mol) was added to the yellow solid compound D (11.5 g, 0.025 mol) obtained in the previous step. The reaction was exothermically intense. The order and temperature of the addition were carefully controlled throughout the process to prevent spillage. Simultaneously, due to the release of acidic gas, tail gas absorption was implemented. The product was concentrated using a rotary evaporator, yielding a crude oily liquid. A single molecule of HCl was bound to the basic site, and the product was purified by slurrying with anhydrous tetrahydrofuran, finally yielding compound C (4.9 g), with a yield of 83%. (3)

[0099]

[0100] The product C obtained in the previous step (4.9 g, 0.02 mol) was added to a 250 mL three-necked flask, along with 29 mL of dry N,N-dimethylformamide. The mixture was stirred to dissolve, and then ammonium chloride (1.9 g, 0.036 mol), TMSN3-azidotrimethylsilane (4.0 g, 0.035 mol), and triethylamine hydrochloride (1.3 g, 0.009 mol) were added sequentially. The mixture was heated to 55 °C and reacted for 15 h. The reaction endpoint was determined by the complete reaction of compound C as detected by thin-layer chromatography. The mixture was then cooled to 25 °C, and 200 mL of water was added. The mixture was extracted with 100 mL of ethyl acetate, and the aqueous layer was discarded. The organic layer was dried over 30 g of anhydrous sodium sulfate for 1.5 h, filtered, and the filtrate was evaporated to dryness under reduced pressure (≥0.08 MPa) at 55 °C to obtain 4.9 g of an oily compound B (yield 89%). (4)

[0102]

[0103] The obtained oily compound of formula B was dissolved in 80 mL of dichloromethane. 2 g of acetic anhydride was added under stirring. The reaction mixture was cooled to 4°C, and 2.5 g of triethylamine was added dropwise at 0°C. After the addition was complete, the reaction mixture was kept at this temperature for 1.5 h. 200 mL of water was added to the reaction mixture, and the layers separated. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure (≥0.08 MPa) at 50°C. 50 mL of ethyl acetate and 80 mL of n-hexane were added, and the mixture was heated to 60°C and stirred for 1.5 h. The mixture was then cooled to 20°C and allowed to crystallize for 2.5 h. The crystals were filtered, and the filter cake was dried under reduced pressure (≥0.08 MPa) at 50°C for 7 h to give 4.9 g of a white solid, compound of formula A, with a yield of 90%. (5)

[0105]

[0106] Add 4.9 g of compound A, 100 mL of ethanol, and 35 mL of water sequentially to a 250 mL three-necked flask, stir to dissolve, then add 4 g of ammonium chloride and 5.5 g of zinc powder. React at 25 °C for 6.5 h. The reaction endpoint is determined by the complete reaction of compound A as detected by thin-layer chromatography. Filter, add 100 mL of water to the filtrate, and extract with 75 mL of dichloromethane twice. Discard the aqueous layer, and evaporate the organic layer to dryness under reduced pressure (≥0.08 MPa) at 50 °C to obtain an oily substance.

[0107] Add 100 mL of ethanol to the obtained oily substance, and then add 5 mL of phosphoric acid ethanol solution (5 mL of 84% phosphoric acid diluted with 50 mL of ethanol) dropwise at 25 °C. Crystallize at this temperature for 1.5 h, filter, and dry the filter cake at 55 °C for 6 h to obtain 4 g of crude oseltamivir methyl ester, with a yield of 89%.

[0108] 4 g of crude oseltamivir methyl ester was added to a 250 mL dry three-necked flask, followed by 125 mL of acetone and 25 mL of water. The mixture was heated to 60 °C to dissolve the ester. 2 g of activated carbon was added, and the mixture was filtered while hot. The filtrate was cooled to 25 ± 2 °C to crystallize for 6 h. The crystals were then filtered under vacuum and dried at 50 °C under reduced pressure for 6 h to obtain 3.7 g of pure product, with a yield of 83.3% and an HPLC purity of 99.80%.

[0109] Example 3

[0110] This embodiment provides a method for preparing oseltamivir methyl ester. (1)

[0112]

[0113] Under nitrogen protection, anhydrous magnesium chloride (4 g, 0.042 mol), toluene (40 mL), and triphenylmethane (17.4 g, 0.067 mol) were added to a 100 mL reaction flask with mechanical stirring, a thermometer, and a reflux condenser. The reaction was continued for 7 h at a temperature below 25 °C. Compound G (oseltamivir impurity) (15.3 g, 0.06 mol) and toluene (40 mL) were added to a 50 mL reaction flask and stirred for 1.5 h until the solid was completely dissolved. The toluene solution of compound G was added to the aforementioned 100 mL reaction flask. Under nitrogen protection, the temperature was raised and maintained at 55 °C for 20 h overnight.

[0114] The solution was cooled to 4°C in a water bath, and the pH was adjusted to 8 with 10% citric acid. The aqueous phase was separated, and extracted twice with toluene (30 ml). The organic phases were combined and washed with water (30 ml). The organic phase was concentrated to dryness to give 18.4 g of oil.

[0115] Add the above oily substance (18.4 g) and toluene (60 ml) to a 250 mL reaction flask and start stirring. Wash with 6 M hydrochloric acid solution (30 ml). Wash the organic phase once with 1 M sodium bicarbonate solution (30 ml), and then once with water (30 ml). Concentrate the organic phase to dryness under reduced pressure to give 20 g of a pale yellow oily compound of formula F. Yield: 66.9%. Purity: 97.6%.

[0116] To the obtained oily compound F (20.0 g, 0.039 mol), 150 mL of toluene was added, and the mixture was stirred to dissolve. The temperature was controlled below 55 °C. Methanesulfonyl chloride (6.7 g, 0.058 mol) and triethylamine hydrochloride (11.0 g, 0.08 mol) were added, and the mixture was heated to 55 °C and reacted for 8.5 h. Thin-layer chromatography was used to determine the endpoint as the intermediate reaction was complete. The reaction mixture was cooled to 25 °C, filtered, and the filtrate was transferred to a separatory funnel. 150 mL of ethyl acetate and 250 mL of saturated brine were added to separate the layers. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure (≥0.08 MPa) at 90 °C to obtain 16 g of a brownish-red oily compound E (yield 83%). (2)

[0118]

[0119] Using methanol and water in a volume ratio of 10:1, 16 g (0.032 mol) of the brownish-red oily compound E obtained in the previous step was added to a solution containing 3.6 g (0.15 mol) of lithium hydroxide hydrolysate. The mixture was stirred to dissolve, heated to 55 °C, and reacted overnight. 14.5 g of a yellow solid, compound D, was obtained, with a yield of 97%.

[0120] Next, using methanol as a solvent, thionyl chloride (SOCl2) (16.6 g, 0.14 mol) was added to the yellow solid compound D (14.5 g, 0.031 mol) obtained in the previous step. The reaction was exothermic, and the order and temperature of the addition were carefully controlled to prevent spillage. Simultaneously, due to the release of acidic gas, tail gas absorption was implemented. The product was concentrated using a rotary evaporator, yielding a crude oily liquid. A single molecule of HCl was bound to the basic site, and the product was purified by slurrying with anhydrous tetrahydrofuran, finally yielding compound C (5.8 g), with a yield of 78%. (3)

[0122]

[0123] The product C obtained in the previous step (5.8 g, 0.024 mol) was added to a 250 mL three-necked flask, along with 35 mL of dry N,N-dimethylformamide. The mixture was stirred to dissolve, and then ammonium chloride (2.0 g, 0.038 mol), TMSN3-azidotrimethylsilane (4.4 g, 0.038 mol), and triethylamine hydrochloride (1.3 g, 0.009 mol) were added sequentially. The mixture was heated to 55 °C and reacted for 14 h. The reaction endpoint was determined by the complete reaction of compound C as detected by thin-layer chromatography. The mixture was then cooled to 25 °C, and 200 mL of water was added. The mixture was extracted with 100 mL of ethyl acetate, and the aqueous layer was discarded. The organic layer was dried over 25 g of anhydrous sodium sulfate for 1.5 h, filtered, and the filtrate was evaporated to dryness under reduced pressure (≥0.08 MPa) at 50 °C to obtain 5.9 g of an oily compound B (yield 88%). (4)

[0125]

[0126] The obtained oily compound of formula B was dissolved in 80 mL of dichloromethane. 2.5 g of acetic anhydride was added under stirring. The reaction mixture was cooled to 4°C, and 2.5 g of triethylamine was added dropwise at 0°C. After the addition was complete, the reaction mixture was kept at this temperature for 2 h. 200 mL of water was added to the reaction mixture, and the layers separated. The aqueous layer was discarded, and the organic layer was evaporated to dryness under reduced pressure (≥0.08 MPa) at 50°C. Then, 50 mL of ethyl acetate and 80 mL of n-hexane were added, and the mixture was heated to 55°C and stirred for 1.5 h. The mixture was then cooled to 20°C and allowed to crystallize for 2.5 h. The crystals were filtered, and the filter cake was dried under reduced pressure (≥0.08 MPa) at 50°C for 6 h to give 6.3 g of a white solid, compound of formula A, with a yield of 93%. (5)

[0128]

[0129] Add 6.3g of compound A, 100mL of ethanol, and 35mL of water sequentially to a 250mL three-necked flask, stir to dissolve, then add 5g of ammonium chloride and 5.5g of zinc powder. React at 25℃ for 5 hours. The reaction endpoint is reached when compound A is completely reacted as detected by thin-layer chromatography. Filter, add 100mL of water to the filtrate, and extract with 75mL of dichloromethane twice. Discard the aqueous layer, and evaporate the organic layer to dryness under reduced pressure (≥0.08MPa) at 50℃ to obtain an oily substance.

[0130] Add 100 mL of ethanol to the obtained oily substance, and then add 4.9 mL of phosphoric acid (84% by mass) diluted with 45 mL of ethanol dropwise at 25 °C. Crystallize at this temperature for 1 h, filter, and dry the filter cake at 55 °C for 6.5 h to obtain 5.1 g of crude oseltamivir methyl ester, with a yield of 88%.

[0131] 5.1 g of crude oseltamivir methyl ester was added to a 250 mL dry three-necked flask, followed by 125 mL of acetone and 25 mL of water. The mixture was heated to 50 °C to dissolve the ester. 2 g of activated carbon was added, and the mixture was filtered while hot. The filtrate was cooled to 25 ± 2 °C to crystallize for 6 h. The crystals were then filtered under vacuum and dried at 50 °C under reduced pressure for 6 h to obtain 4.6 g of pure product, with a yield of 85% and an HPLC purity of 99.80%.

[0132] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing methyl oseltamivir, characterized in that, The preparation method is as follows: Compound E is hydrolyzed with lithium hydroxide in a mixed solution of methanol and water at a volume ratio of 10:1 at 40-60°C for 10-15 h to obtain compound D. The molar ratio of compound E to lithium hydroxide is 1:0.4-0.

6. Then, compound D is deprotected and esterified with thionyl chloride in methanol at a molar ratio of 1:0.4-0.8 to obtain compound C. ； Compound C was reacted with azidotrimethylsilane in N,N-dimethylformamide at 50-60°C for 10-18 h in the presence of ammonium chloride and triethylamine to prepare compound B. The molar ratio of compound C to azidotrimethylsilane, ammonium chloride, and triethylamine was 1:1.5-2:1.5-2:0.4-0.

6. ； Compound A was prepared by reacting compound B with acetic anhydride in a molar ratio of 1:1 to 1.5 in dichloromethane and / or trichloromethane at -5°C to 10°C for 0.5 to 2 h in the presence of triethylamine. ； The compound shown in Formula A is reacted in a mixed solution of ethanol and water at 20-30°C for 4-6 hours in the presence of zinc powder and ammonium chloride. After the reaction is completed, a phosphoric acid ethanol solution with a mass concentration of 83%-85% is added to obtain the methyl oseltamivir. The molar ratio of the compound shown in Formula A to zinc powder is 1:4-6; the molar ratio of the compound shown in Formula A to ammonium chloride is 1:4-6. 。 2. The preparation method according to claim 1, characterized in that, The preparation process of compound E is as follows: compound G and triphenylmethylamine are reacted in toluene in the presence of magnesium chloride to obtain compound F, and then compound F is reacted with methanesulfonyl chloride in toluene in the presence of triethylamine hydrochloride to obtain compound E. The molar ratio of compound G to triphenylmethylamine and magnesium chloride is 1:1~1.5:0.8~1; The molar ratio of compound F to methanesulfonyl chloride and triethylamine hydrochloride is 1:1.1~1.5:1.5~2.5; 。 3. A method for preparing methyl oseltamivir, characterized in that, The preparation method includes the following steps: (1) Compound G and triphenylmethylamine were reacted in toluene at 50-60°C for 20-25 h in the presence of magnesium chloride, with the molar ratio of compound G to triphenylmethylamine and magnesium chloride being 1:1~1.5:0.8~1, to obtain compound F. Then, compound F and methanesulfonyl chloride were reacted in toluene at 50-60°C for 6-10 h in the presence of triethylamine hydrochloride, with the molar ratio of compound F to methanesulfonyl chloride and triethylamine hydrochloride being 1:1.1~1.5:1.5~2.5, to obtain compound E. ； (2) Compound E is hydrolyzed with lithium hydroxide in a mixed solution of methanol and water at a volume ratio of 10:1 at 40-60°C for 10-15 h to obtain compound D. The molar ratio of compound E to lithium hydroxide is 1:0.4-0.

6. Then, compound D is deprotected and esterified with thionyl chloride in methanol at a molar ratio of 1:0.4-0.8 to obtain compound C. ； (3) Compound C is reacted with azidotrimethylsilane in N,N-dimethylformamide at 50-60°C for 10-18 h in the presence of ammonium chloride and triethylamine to prepare compound B. The molar ratio of compound C to azidotrimethylsilane, ammonium chloride and triethylamine is 1:1.5-2:1.5-2:0.4-0.

6. ； (4) Compound B of formula B with a molar ratio of 1:1 to 1.5 is reacted with acetic anhydride in dichloromethane and / or trichloromethane at -5°C to 10°C for 0.5 to 2 h in the presence of triethylamine to prepare compound A; ； (5) The compound shown in Formula A is reacted in a mixed solution of ethanol and water in the presence of zinc powder and ammonium chloride at 20-30°C for 4-6 hours. After the reaction is completed, a phosphoric acid ethanol solution with a mass concentration of 83%-85% is added to obtain the methyl oseltamivir. The molar ratio of the compound shown in Formula A to zinc powder is 1:4-6; the molar ratio of the compound in Formula A to ammonium chloride is 1:4-6. 。

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