Preparation method of oseltamivir chiral isomer

Abstract

According to the preparation method of the oseltamivir chiral isomer, a three-membered ring compound A is subjected to ring opening to obtain a compound B, the compound B reacts with substituent sulfonyl chloride under the action of an acid-binding agent to obtain a compound C, a compound D with inverted configuration is obtained under the action of tert-butylamine or allyl amine, then the compound D reacts with acetic anhydride or acetyl chloride to obtain a compound E, and the compound E reacts with acetic anhydride or acetyl chloride to obtain the oseltamivir chiral isomer. Deprotecting the compound E to obtain a compound F, finally obtaining a compound G under the catalytic action of a positive ion trapping agent and a catalyst, and treating with an ethanol solution of hydrogen chloride to obtain the oseltamivir non-enantiomer H, namely a hydrochloride form. A white solid obtained after purification by an ethanol solution of hydrogen chloride and ethyl acetate is easy to store; the preparation method disclosed by the invention avoids introduction of azido, raw materials are easy to obtain, reaction conditions are mild, the method is safe and easy to operate, the product purity is high, and solid storage is more convenient.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a method for preparing an oseltamivir chiral isomer. Background Art

[0002] Oseltamivir phosphate, English name: Oseltamivir phosphate, chemical name: (3R,4R,5S)-4-acetamide-5-amino-3 (1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate, is an antiviral drug developed by Roche in Switzerland for the prevention and treatment of influenza. It was officially approved by the FDA in 1999. Since its launch, its global annual sales have exceeded US$20 billion, occupying a major share of the anti-influenza drug market. As a reserve drug for influenza and avian influenza outbreaks, it has broad market demand and market prospects.

[0003] There are three chiral centers in the structure of oseltamivir, one enantiomer and six diastereomers. Usually, oseltamivir refers to chiral carbon corresponding configurations of 3R, 4R, and 5S. The structural formula is as follows:

[0004]

[0005] In 2017, Synbos Bio reported a method for preparing this isomer, as described in patent CN108047077A, the route is as follows:

[0006]

[0007] The corresponding configurations of the chiral carbon of the isomer are 3R, 4R, and 5R. The three-membered ring compound 1 is opened with sodium azide, the configuration is reversed, and the compound 3 is obtained by Staudinger reaction and reaction with Boc anhydride. Under the action of an acid-binding agent and methanesulfonyl chloride, compound 4 is formed, and then under the action of sodium azide, the configuration is reversed to obtain compound 5, and then the azide group is reduced and reacted with acetic anhydride to obtain compound 6, and finally the Boc protection is removed to obtain compound 7. However, this method uses the more dangerous sodium azide reagent twice, and the operation is complicated. Summary of the invention

[0008] In view of the above-mentioned shortcomings of the prior art, the object of the present invention is to provide a method for preparing chiral isomers of oseltamivir, so as to solve the technical problems of harsh production conditions, dangerous raw materials and complicated operation methods in the prior art.

[0009] To achieve the above object and other related objects, the present invention provides a method for preparing a chiral isomer of oseltamivir, comprising the following steps:

[0010] S1, a three-membered ring compound A undergoes a ring-opening reaction with a secondary amine to obtain a compound B;

[0011] S2, the compound B reacts with a substituted sulfonyl chloride to obtain a compound C;

[0012] S3, compound C undergoes configuration inversion under the action of tert-butylamine or allylamine to obtain compound D;

[0013] S4, reacting the compound D with acetic anhydride or acetyl chloride to obtain compound E;

[0014] S5, deprotecting the compound E to obtain compound F;

[0015] S6, compound F is reacted with a positive ion capture agent and a catalyst to obtain compound G;

[0016] The reaction formula is as follows:

[0017]

[0018] Among them, R 1 is selected from one of allyl and tert-butyl; R 2 is selected from one of allyl and tert-butyl; R 3 is selected from one of methyl, ethyl, phenyl and p-tolyl; R 4 Selected from one of allyl and tert-butyl.

[0019] The present invention also provides an intermediate compound of the chiral isomer of oseltamivir prepared by the preparation method as described above, and the structural formula is:

[0020]

[0021] Among them, R 1 is selected from one of allyl and tert-butyl; R 2 is selected from one of allyl and tert-butyl; R 4 Selected from one of allyl and tert-butyl.

[0022] As described above, the method for preparing the chiral isomers of oseltamivir of the present invention has the following beneficial effects:

[0023] The preparation method of the chiral isomer of oseltamivir of the present invention comprises the following steps: ring-opening a three-membered ring compound A to obtain a compound B, reacting the compound C with a substituted sulfonyl chloride, reacting the compound C with tert-butylamine or allylamine to obtain a compound D with inverted configuration, reacting the compound D with acetic anhydride or acetyl chloride to obtain a compound E, deprotecting the compound E, and finally removing the allyl group or tert-butyl group under the catalytic action of a positive ion trapping agent and a catalyst to obtain a chiral isomer compound G of oseltamivir; further, treating the compound A with an ethanol solution of hydrogen chloride to obtain an oseltamivir non-corresponding isomer H (in the form of hydrochloride), and purifying the compound C with an ethanol solution of hydrogen chloride and ethyl acetate to obtain a white solid that is easy to store; the preparation method of the present invention avoids the introduction of an azide group, the reaction raw materials are easily available, the reaction conditions are mild, and the compound is safe and easy to operate.

[0024] The invention provides a simple and clear synthesis method, the process operation of which is safe and easy to operate, the product purity is high, and the solid storage is more convenient. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 is the mass spectrum of compound 5 of the present invention.

[0026] Figure 2 is the hydrogen spectrum of compound 5 of the present invention.

[0027] Figure 3 This is the carbon spectrum of compound 5 of the present invention.

[0028] Figure 4 is the mass spectrum of compound 8 of the present invention.

[0029] Figure 5 It is the liquid phase spectrum of compound 8 of the present invention.

[0030] Figure 6 is the hydrogen spectrum of compound 8 of the present invention.

[0031] Figure 7 This is the carbon spectrum of compound 8 of the present invention. DETAILED DESCRIPTION

[0032] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present invention.

[0033] Please refer to the attached drawings. It should be noted that the illustrations provided in this embodiment are only used to illustrate the basic concept of the present invention in a schematic manner, and the drawings only show the components related to the present invention rather than the number, shape and size of the components in actual implementation. In actual implementation, the type, quantity and proportion of each component may be changed arbitrarily, and the component layout may also be more complicated.

[0034] The first aspect of the present invention provides a method for preparing a chiral isomer of oseltamivir, comprising the following steps:

[0035] S1, subjecting the three-membered ring compound A to a ring-opening reaction with a secondary amine to obtain a compound B;

[0036] S2, the compound B reacts with a substituted sulfonyl chloride to obtain a compound C;

[0037] S3, compound C undergoes configuration inversion under the action of tert-butylamine or allylamine to obtain compound D;

[0038] S4, reacting the compound D with acetic anhydride or acetyl chloride to obtain compound E;

[0039] S5, deprotecting the compound E to obtain compound F;

[0040] S6, compound F is reacted with a positive ion capture agent and a catalyst to obtain compound G;

[0041] The reaction formula is as follows:

[0042]

[0043] Among them, R 1 is selected from one of allyl and tert-butyl; R 2 is selected from one of allyl and tert-butyl; R 3 is selected from one of methyl, ethyl, phenyl and p-tolyl; R 4 Selected from one of allyl and tert-butyl.

[0044] In the preparation method of the present invention, the ring-opening reaction in step S1 is carried out under the action of magnesium chloride.

[0045] Wherein, the molar ratio of the amount of magnesium chloride to compound A is 1.1 to 2.0:1. For example, 1.1 to 1.2:1, 1.2 to 1.4:1, 1.4 to 1.5:1, 1.5 to 1.6:1, 1.6 to 1.8:1 or 1.8 to 2.0:1. In a preferred embodiment of the present invention, the molar ratio of the amount of magnesium chloride to compound A is 1.4 to 1.5:1.

[0046] The solvent for the ring-opening reaction in step S1 is selected from one or more of benzene, toluene and xylene. In a preferred embodiment of the present invention, the solvent for the ring-opening reaction is toluene.

[0047] In step S1, the secondary amine is selected from diallylamine, di-tert-butylamine or tert-butylallylamine.

[0048] The molar ratio of compound A to the secondary amine in step S1 is 1:1.9-3.0. For example, 1.9-2.0, 2.0-2.1, 2.1-2.2, 2.2-2.3, 2.3-2.4, 2.4-2.5, 2.5-2.6, 2.6-2.7, 2.7-2.8, 2.8-2.9 or 2.9-3.0. In a preferred embodiment of the present invention, the molar ratio of compound A to diallylamine is 1:2.8.

[0049] The temperature of the ring-opening reaction in step S1 is 45-55°C, for example 45-50°C or 50-55°C.

[0050] The specific process of step S1 is: the three-membered ring compound A and diallylamine are heated in a solvent under the action of magnesium chloride to perform a ring-opening reaction to obtain a compound (3R, 4S, 5R)-B. After the reaction is completed, the weak alkalinity of the product is used to first adjust the pH to <5, with the optimal pH being 1 to 3, and the pH of the aqueous phase is then adjusted to >10, with the optimal pH being 11 to 14. The product B can be obtained by solvent extraction and concentration.

[0051] In the preparation method of the present invention, the substituent sulfonyl chloride in step S2 is selected from one of methanesulfonyl chloride, ethylsulfonyl chloride, phenylsulfonyl chloride and p-toluenesulfonyl chloride. In a preferred embodiment of the present invention, the substituent sulfonyl chloride in step S2 is methanesulfonyl chloride.

[0052] In step S2, the reaction between compound B and substituted sulfonyl chloride is carried out under the action of an acid binding agent.

[0053] Wherein, the acid binding agent is selected from one of triethylamine, diisopropylethylamine and pyridine.

[0054] The molar ratio of the amount of the acid binding agent to the substituted sulfonyl chloride is 1 to 3: 1. For example, 1 to 1.3: 1, 1.3 to 1.5: 1, 1.5 to 1.8: 1, 1.8 to 2: 1, 2 to 2.3: 1, 2.3 to 2.5: 1, 2.5 to 2.8: 1 or 2.8 to 3: 1. In a preferred embodiment of the present invention, the amount of the acid binding agent or the molar ratio of the amount of the acid binding agent to the substituted sulfonyl chloride is 1.3: 1.

[0055] The solvent for the reaction of compound B with the substituted sulfonyl chloride in step S2 is an aprotic solvent. The aprotic solvent is specifically selected from one or more of dichloromethane, chloroform, tetrahydrofuran, ethyl acetate, methyl tert-butyl ether, and toluene;

[0056] The molar ratio of compound B to substituted sulfonyl chloride in step S2 is 1:0.8 to 1:3. For example, 1:0.8 to 1:1, 1:1 to 1:1.2, 1:1.2 to 1:1.5, 1:1.5 to 1:1.8, 1:1.8 to 1:2, 1:2 to 1:2.2, 1:2.2 to 1:2.5, 1:2.5 to 1:2.8 or 1:2.8 to 1:3. In a preferred embodiment of the present invention, the molar ratio of compound B to substituted sulfonyl chloride is 1:1.5.

[0057] The temperature for the reaction of compound B with the substituted sulfonyl chloride in step S2 is 0-25° C., for example, 0-5° C., 5-10° C., 10-15° C., 15-20° C. or 20-25° C. Specifically, the temperature is controlled at 0-10° C. during the feeding stage, and the temperature is controlled at 10-25° C. after the feeding is completed.

[0058] The specific process of step S2 is: compound B reacts with p-toluenesulfonyl chloride, methanesulfonyl chloride, phenylsulfonyl chloride, and ethylsulfonyl chloride in dichloromethane under the action of an acid-binding agent to obtain a sulfonyl-protected compound (3R, 4S, 5R)-C. After the reaction is completed, water is added, the liquids are separated, and the organic phase is concentrated to obtain product C.

[0059] In the preparation method of the present invention, the molar ratio of the compound C to tert-butylamine or allylamine in step S3 is 1:0.8 to 1:5. For example, 1:0.8 to 1:1, 1:1 to 1:1.5, 1:1.5 to 1:2, 1:2 to 1:2.5, 1:2.5 to 1:3, 1:3 to 1:3.5, 1:3.5 to 1:4, 1:4 to 1:4.5 or 1:4.5 to 1:5. In a preferred embodiment of the present invention, the molar ratio of the compound C to tert-butylamine or allylamine is 1:2 or 1:3.

[0060] The solvent for the configuration inversion reaction in step S3 is selected from one or more of methanol, ethanol, and isopropanol. In a preferred embodiment of the present invention, the solvent for the configuration inversion reaction is methanol.

[0061] The reaction temperature of the configuration inversion in step S3 is 55-65°C, for example 55-60°C or 60-65°C.

[0062] The specific process of step S3 is as follows: Compound C is heated and stirred in a solvent under the action of tert-butylamine to undergo an SN2 configuration inversion reaction (Walden inversion) to obtain a configuration-inverted compound (3R, 4R, 5R)-D. After the reaction is completed, the product C can be obtained by direct decompression and concentration.

[0063] In the preparation method of the present invention, in step S4, the compound D reacts with acetic anhydride or acetyl chloride under the action of a catalyst N,N-dimethylpyridine.

[0064] Wherein, the molar ratio of the compound D to N,N-dimethylpyridine is 1:0.01 to 1:1. For example, 1:0.01 to 1:0.03, 1:0.03 to 1:0.05, 1:0.05 to 1:0.08, 1:0.08 to 1:0.1, 1:0.1 to 1:0.3, 1:0.3 to 1:0.5, 1:0.5 to 1:0.8 or 1:0.8 to 1:1.0. In a preferred embodiment of the present invention, the molar ratio of the compound D to N,N-dimethylpyridine is 1:0.005.

[0065] In step S4, the compound D is reacted with acetic anhydride in the presence of sodium acetate. The molar ratio of the compound D to sodium acetate is 1:1-1:2. For example, 1:1-1:1.03, 1:1.03-1:1.06, 1:1.06-1:1.09, 1:1.09-1:1.1, 1:1.1-1:1.2, 1:1.2-1:1.4, 1:1.4-1:1.6, 1:1.6-1:1.8 or 1:1.8-1:2. In a preferred embodiment of the present invention, the molar ratio of the compound D to sodium acetate is 1:1.06.

[0066] When the compound D reacts with acetic anhydride in step S4, the molar ratio of acetic anhydride to compound D is 2 to 20:1. For example, 2 to 4:1, 4 to 6:1, 6 to 8:1, 8 to 10:1, 10 to 12:1, 12 to 14:1, 14 to 16:1, 16 to 18:1 or 18 to 20:1. In a preferred embodiment of the present invention, the molar ratio of acetic anhydride to compound D is 8:1.

[0067] The reaction of compound D and acetic anhydride in step S4 is heated to reflux. The specific temperature is 135-145°C, for example, 135-137°C, 137-139°C, 139-141°C, 141-143°C or 143-145°C.

[0068] In step S4, the compound D reacts with acetyl chloride in the presence of a weak base and an aprotic solvent. The weak base is selected from one or more of sodium acetate, potassium acetate, sodium bicarbonate, triethylamine, diisopropylethylamine, sodium carbonate, and potassium carbonate. The aprotic solvent is selected from one or more of tetrahydrofuran, toluene, dichloromethane, and 1,4-dioxane.

[0069] In step S4, the reaction temperature of the compound D and acetyl chloride is heated to reflux state according to the selected solvent.

[0070] When the compound D reacts with acetyl chloride in step S4, the molar ratio of acetyl chloride to compound D is 1:1 to 5:1. For example, 1:1 to 1.5:1, 1.5:1 to 2:1, 2:1 to 2.5:1, 2.5:1 to 3:1, 3:1 to 3.5:1, 3.5:1 to 4:1, 4:1 to 4.5:1 or 4.5:1 to 5:1. In a preferred embodiment of the present invention, the molar ratio of acetyl chloride to compound D is 1.5:1 to 2:1.

[0071] In a preferred embodiment of the present invention, the specific process of step S4 is: compound D and acetic anhydride (both solvent and reactant) are reacted with sodium acetate, 4-N,N-dimethylpyridine (DMAP) as a catalyst, and stirred under reflux to obtain acetyl-protected compound (3R, 4R, 5R)-E. After the reaction is completed, the reaction is concentrated, the pH is adjusted to >8 with sodium hydroxide solution, the optimal pH is 9-12, and the organic solvent is used for extraction and concentration to obtain product E.

[0072] In the preparation method of the present invention, the deprotection of compound E in step S5 is carried out under the action of trifluoroacetic acid or ethanolic hydrogen chloride solution or methanolic hydrogen chloride solution. In a preferred embodiment of the present invention, the deprotection of compound E is carried out under the action of trifluoroacetic acid.

[0073] The concentration of the hydrogen chloride ethanol solution is 8wt% to 12wt%. For example, 8wt% to 9wt%, 9wt% to 10wt%, 10wt% to 11wt% or 11wt% to 12wt%. In a preferred embodiment of the present invention, the concentration of the hydrogen chloride ethanol solution is 10wt%. Specifically, it is prepared by dissolving 1g of hydrogen chloride in 9g of ethanol.

[0074] The concentration of the hydrogen chloride methanol solution is 8wt% to 12wt%. For example, 8wt% to 9wt%, 9wt% to 10wt%, 10wt% to 11wt% or 11wt% to 12wt%. In a preferred embodiment of the present invention, the concentration of the hydrogen chloride methanol solution is 10%. Specifically, 1g of hydrogen chloride is dissolved in 9g of methanol to prepare it.

[0075] In step S5, the molar ratio of compound E to trifluoroacetic acid is 1:2 to 1:50. For example, 1:2 to 1:5, 1:5 to 1:10, 1:10 to 1:15, 1:15 to 1:20, 1:20 to 1:25, 1:25 to 1:30, 1:30 to 1:35, 1:35 to 1:40, 1:10 to 1:45 or 1:45 to 1:50. In a preferred embodiment of the present invention, the molar ratio of compound E to trifluoroacetic acid is 1:10 to 1:15.

[0076] The molar ratio of compound E to hydrogen chloride in the hydrogen chloride ethanol solution or the hydrogen chloride methanol solution in step S5 is 1:2 to 1:50. For example, 1:2 to 1:5, 1:5 to 1:10, 1:10 to 1:15, 1:15 to 1:20, 1:20 to 1:25, 1:25 to 1:30, 1:30 to 1:35, 1:35 to 1:40, 1:10 to 1:45 or 1:45 to 1:50. In a preferred embodiment of the present invention, the molar ratio of compound E to hydrogen chloride in the hydrogen chloride ethanol solution or the hydrogen chloride methanol solution is 1:10 to 1:15.

[0077] The deprotection temperature in step S5 is 45-55°C, for example 45-50°C or 50-55°C.

[0078] The specific process of step S5 is as follows: Compound E is heated and stirred under the action of trifluoroacetic acid or hydrogen chloride ethanol solution or hydrogen chloride methanol solution to remove the tert-butyl group to obtain compound (3R, 4R, 5R)-F. After the reaction is completed, the mixture is concentrated, and the pH is adjusted to >8 with sodium hydroxide solution, with the optimal pH being 10-14. The mixture is extracted with toluene and concentrated to obtain product F.

[0079] In the preparation method of the present invention, the positive ion capture agent in step S6 is 1,3-dimethylbarbituric acid (NDMBA).

[0080] The molar ratio of the compound F to the positive ion capture agent in step S6 is 1:1-2, for example, 1:1-1.2, 1:1.2-1.4, 1:1.4-1.6, 1:1.6-1.8 or 1:1.8-2.

[0081] The catalyst in step S6 is palladium acetate and triphenylphosphine.

[0082] The molar ratio of palladium acetate to triphenylphosphine is 1:1 to 1:10, for example 1:1 to 1:2, 1:2 to 1:4, 1:4 to 1:6, 1:6 to 1:8 or 1:8 to 1:10. In a preferred embodiment of the present invention, the molar ratio of palladium acetate to triphenylphosphine is 1:2.

[0083] In step S6, the molar ratio of the catalyst to compound F is 0.5% to 5%. For example, 0.5% to 1%, 1% to 1.5%, 1.5% to 2%, 2% to 2.5%, 2.5% to 3%, 3% to 3.5%, 3.5% to 4%, 4% to 4.5% or 4.5% to 5%. In a preferred embodiment of the present invention, the molar ratio of the catalyst to compound F is 1%.

[0084] The reaction temperature of the compound F, the positive ion capture agent and the catalyst in step S6 is 25-35°C, for example 25-30°C or 30-35°C.

[0085] In the preparation method of the present invention, the compound G obtained in step S6 is treated with an ethanol solution of hydrogen chloride to obtain its hydrochloride form, i.e., compound H, and the reaction formula is as follows:

[0086]

[0087] The preparation of compound H specifically includes the steps of: dissolving compound G in ethyl acetate, slowly adding ethanol solution of hydrogen chloride to adjust the solution pH to <5, keeping warm at -5 to 0°C for crystallization, filtering and washing to obtain compound H.

[0088] The ratio of the compound G to ethyl acetate is 1 g: (2-4) mL, for example, 1 g: (2-2.5) mL, 1 g: (2.5-3) mL, 1 g: (3-3.5) mL or 1 g: (3.5-4) mL.

[0089] The washing is carried out using ethyl acetate and / or ethanol.

[0090] The specific process of step S6 is as follows: Compound F is subjected to removal of allyl group under the catalytic action of palladium acetate and triphenylphosphine with 1,3-dimethylbarbituric acid (NDMBA) as a positive ion capture agent to obtain a crude compound G. After the reaction is completed, the compound is concentrated under reduced pressure, ethyl acetate (2 to 4 times the mass volume) is added to dissolve, the pH is adjusted to <5 with a hydrogen chloride ethanol solution, the optimal pH is 1 to 2, the crystallization is stirred at -5 to 0°C, and the white solid product H is obtained by filtration, and the purity can reach more than 96%.

[0091] The second aspect of the present invention provides an intermediate compound of the chiral isomer of oseltamivir prepared by the preparation method as described above, and the structural formula is:

[0092]

[0093] Among them, R 1 is selected from one of allyl and tert-butyl; R 2 is selected from one of allyl and tert-butyl; R 4 Selected from one of allyl and tert-butyl.

[0094] In the following examples, unless otherwise specified, all reaction raw materials are commercially available products.

[0095] Example 1

[0096] Compound 1 (50.00 g, 0.20 mol) was dissolved in toluene (200 ml), anhydrous magnesium chloride (28.10 g, 0.29 mmol) was added, nitrogen was protected, and the mixture was stirred at room temperature. Diallylamine (38.20 g, 0.39 mol) was added dropwise over 5 to 10 min. The reaction solution was heated to 50 ° C for 4 hours, cooled to 0 to 5 ° C, 1 mol / L hydrochloric acid was added dropwise to adjust the pH to 1 to 2, and the liquids were separated. The aqueous phase was adjusted to pH 13 to 14 with 10% sodium hydroxide solution, and extracted twice with 100 ml of ethyl acetate. The organic phases were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain 25.31 g of compound 2 (3R, 4S, 5R) with a purity of 96% and a yield of 36%.

[0097]

[0098] Compound 2 (12.50 g, 35.6 mmol) was dissolved in dichloromethane (50 ml) under nitrogen protection and stirred at 0-5°C. Methanesulfonyl chloride (8.55 g, 74.7 mmol) and triethylamine (8.62 g, 85.4 mmol) were added dropwise in sequence. The internal temperature was controlled to be less than 10°C. After the addition was completed, the temperature was slowly raised to 25°C and stirred for 1 h. Water (25 ml) was added and the mixture was stirred for separation. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure. 15.03 g of light yellow liquid compound 3 (3R, 4S, 5R) was separated by column chromatography with a purity of 95% and a yield of 98%.

[0099]

[0100] Compound 3 (15.03 g, 34.9 mmol) and tert-butylamine (9.57 g, 130 mmol) were sequentially added to CH3OH (150 ml) under nitrogen protection. The temperature was raised to 60°C and stirred for 2 hours. The mixture was concentrated under reduced pressure and separated by column chromatography to obtain 13.1 g of light yellow liquid compound 4 (3R, 4R, 5R) with a purity of 96% and a yield of 93%.

[0101]

[0102] Compound 4 (13.10 g, 33.2 mmol), NaOAc (2.82 g, 34.4 mmol) and DMAP (0.2 g, 1.7 mmol) were added to Ac2O (35.12 g, 340 mmol) in sequence, and the mixture was heated to reflux and stirred for 12 hours under nitrogen protection, cooled to 0-5°C, and 10% sodium hydroxide aqueous solution was added dropwise to adjust the pH to 9-10, extracted with ethyl acetate (50 ml), dried with sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 10.01 g of yellow oily liquid compound 5 (3R, 4R, 5R) with a purity of 98% and a yield of 67%. [M+1] + 449.2117. 1 H-NMR (400Mz, CDCl3): δ6.90(s,1H),5.85-5.73(m,2H),5.28-5.01(m,4H),4.30-4.10(m,3H),3.90-2 .80(m,8H),2.62-2.47(m,1H),2.18(s,3H),1.70-1.36(m,13H),1.31-1.25(m,3H),0.92-0.84(m,6H). 13 C-NMR (400Mz, CDCl3): δ172.8,166.8,139.8,138.3,132.9,119.8,117.0,79. 3,61.3,54.8,54.0,49.5,40.5,32.0,31.2,27.6,26.5,25.5,14.7,9.9,9.8.

[0103]

[0104] Compound 5 (5.00 g, 11.1 mmol) was dissolved in trifluoroacetic acid (10 ml), heated to 50°C under nitrogen, stirred for 2 hours, concentrated under reduced pressure, adjusted to pH 13-14 with 10% sodium hydroxide solution, extracted twice with toluene (20 ml), washed with saturated sodium chloride solution (10 ml), dried with sodium sulfate, concentrated under reduced pressure, and separated by column chromatography to obtain 4.02 g of yellow oily liquid compound 6 (3R, 4R, 5R, purity 98%, yield 92%.

[0105]

[0106] Compound 6 (4.02 g, 10.2 mmol), NDMBA (1.62 g, 10.4 mmol), palladium acetate (22.9 mg, 0.10 mmol) and triphenylphosphine (53.5 mg, 0.20 mmol) were added to ethanol (25 ml) in sequence, and the mixture was heated to 30°C under nitrogen protection, and stirred for 2 hours. The crude product compound 7 (3R, 4R, 5R) after concentration under reduced pressure was added with ethyl acetate (10 ml), and hydrogen chloride ethanol solution was added dropwise to adjust the pH to 1-2, and stirred for 1-2 hours at 0°C, filtered, and washed with a small amount of ethyl acetate to obtain 1.15 g of a white solid (compound 8) with a purity of 96% and a two-step yield of 33%. [M+1] + 313.1617.

[0107] 1 H-NMR (400Mz, d 6 -DMSO): δ8.40 (d, J = 8.0 Hz, 1H), 8.31 (brs, 3H, active hydrogen), 6.71 (s, 1H), 4.41 (d, J = 7.6 Hz, 1H), 4.17-4.04 (m, 3H), 3.48-3.42 (m, 1H), 3.21-3.17 (m, 1H), 2.60 (dd, J = 5.2 Hz, 17.6 Hz, 1H), 2.29 (m, 1H), 1.88 (s, 3H), 1.70 (m, 1H), 1.54 (m, 2H), 1.38 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 0.85 (dt, J = 7.2 Hz, 6H).

[0108] 13 C-NMR (400Mz, d 6 -DMSO): δ170.0,165.2,135.0,129.1,79.5,72.3,60.6,53.6,45.1,29.9,25.6,24.8,23.1,14.1,9.6,9.4.

[0109]

[0110] Example 2

[0111] Compound 1 (50.00 g, 0.20 mol) was dissolved in toluene (200 ml), anhydrous magnesium chloride (28.10 g, 0.29 mmol) was added, nitrogen was protected, and the mixture was stirred at room temperature. Diallylamine (55.00 g, 0.56 mol) was added dropwise over 5 to 10 min. The reaction solution was heated to 50 ° C and reacted for 4 hours. The temperature was lowered to 0 to 5 ° C, 1 mol / L hydrochloric acid was added dropwise to adjust the pH to 1 to 2, and the liquids were separated. The aqueous phase was adjusted to pH 13 to 14 with 10% sodium hydroxide solution, and extracted twice with 100 ml of ethyl acetate. The organic phases were combined, dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain 56.30 g of compound 2 with a purity of 95% and a yield of 80%.

[0112]

[0113] Compound 2 (56.30 g, 0.16 mol) was dissolved in dichloromethane (200 ml) under nitrogen protection and stirred at 0-5°C. Methanesulfonyl chloride (27.50 g, 0.24 mmol) and triethylamine (32.30 g, 0.32 mmol) were added dropwise in sequence. The internal temperature was controlled to be less than 10°C. After the addition was completed, the temperature was slowly raised to 25°C and stirred for 1 h. Water (100 ml) was added and stirred for separation. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 83.40 g of compound 3, which was directly reacted in the next step.

[0114] Compound 3 (83.40 g) and tert-butylamine (23.60 g, 0.32 mol) were added to CH3OH (250 ml) in sequence, and refluxed and stirred for 2 hours under nitrogen protection, and concentrated under reduced pressure to obtain 63.01 g of compound 4, which was directly used for the next step reaction.

[0115] Compound 4 (63.01 g), NaOAc (13.80 g, 0.17 mol) and DMAP (1.00 g, 8 mmol) were added to Ac2O (133.00 g, 1.3 mol) in sequence, protected by nitrogen, heated to reflux with stirring for 12 hours, concentrated under reduced pressure, cooled to 0-5°C, and 10% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 9-10. The mixture was extracted with ethyl acetate (200 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure to obtain 53.91 g of yellow oily liquid compound 5 with a yield of 75% in three steps.

[0116]

[0117] Compound 5 (53.91 g, 0.12 mol) was dissolved in trifluoroacetic acid (100 ml), kept warm under nitrogen, heated to 50°C, stirred for 2 to 3 hours, concentrated under reduced pressure, adjusted pH to 13 to 14 with 10% sodium hydroxide solution, stirred for 10 min and then retested, extracted twice with toluene (200 ml), washed with saturated sodium chloride solution (100 ml), dried over sodium sulfate, and concentrated under reduced pressure to obtain 44.71 g of yellow oily liquid 6 with a yield of 95%.

[0118]

[0119] Compound 6 (39.20 g, 0.10 mol), NDMBA (16.23 g, 0.11 mmol), palladium acetate (0.23 g, 1.0 mmol) and triphenylphosphine (0.54 g, 2.0 mmol) were added to ethanol (250 ml) in sequence, protected by nitrogen, heated to 30°C, stirred for 2 hours, concentrated under reduced pressure, added with ethyl acetate (80 ml), and added with hydrogen chloride ethanol solution dropwise to adjust the pH to 1-2. The mixture was stirred at -5-0°C for 12 hours, filtered, and washed with a small amount of ethyl acetate and ethanol to obtain 20.90 g of a nearly white solid (compound 8) with a yield of 60% and a purity of >96%.

[0120]

[0121] In summary, the preparation method of the chiral isomer of oseltamivir of the present invention is to open the three-membered ring compound A under the action of diallylamine to obtain compound B, react with sulfonyl chloride under the action of an acid binding agent to obtain compound C, obtain compound D with inverted configuration under the action of tert-butylamine or allylamine, and then react with acetic anhydride or acetyl chloride to obtain compound E, remove the tert-butyl protection through the action of trifluoroacetic acid to obtain compound F, and finally remove the allyl group under the catalytic action of 1,3-dimethylbarbituric acid (NDMBA) as a positive ion capture agent and palladium acetate and triphenylphosphine, and treat with an ethanol solution of hydrogen chloride to obtain oseltamivir non-corresponding isomer H (hydrochloride form); the white solid obtained after purification by an ethanol solution of hydrogen chloride and ethyl acetate is easy to store and can be better used for product quality control of oseltamivir. Therefore, the present invention effectively overcomes various shortcomings in the prior art and has a high industrial utilization value.

[0122] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A method for preparing a chiral isomer of oseltamivir, characterized in that: The steps include: S1, a three-membered ring compound A undergoes a ring-opening reaction with a secondary amine to obtain a compound B; S2, the compound B reacts with a substituted sulfonyl chloride to obtain a compound C; S3, compound C undergoes configuration inversion under the action of tert-butylamine or allylamine to obtain compound D; S4, reacting the compound D with acetic anhydride or acetyl chloride to obtain compound E; S5, deprotecting the compound E to obtain compound F; S6, compound F is reacted with a positive ion capture agent and a catalyst to obtain compound G; The reaction formula is as follows: Among them, R 1 is selected from one of allyl and tert-butyl; R 2 is selected from one of allyl and tert-butyl; R 3 is selected from one of methyl, ethyl, phenyl and p-tolyl; R 4 Selected from one of allyl and tert-butyl.

2. The method for preparing the chiral isomer of oseltamivir according to claim 1, characterized in that: The ring-opening reaction in step S1 is carried out under the action of magnesium chloride; and / or, the secondary amine in step S1 is selected from diallylamine, di-tert-butylamine or tert-butylallylamine; and / or, the ring-opening reaction in step S1 further comprises a solvent, and the solvent is selected from one or more of benzene, toluene and xylene; and / or, the molar ratio of compound A to secondary amine in step S1 is 1:1.9-3.0; And / or, the temperature of the ring-opening reaction in step S1 is 45-55°C.

3. The method for preparing the chiral isomer of oseltamivir according to claim 1, characterized in that: The substituted sulfonyl chloride in step S2 is selected from methanesulfonyl chloride, ethylsulfonyl chloride, phenylsulfonyl chloride, and p-toluenesulfonyl chloride; And / or, the reaction of compound B with substituted sulfonyl chloride in step S2 is carried out under the action of an acid binding agent; and / or, the solvent for the reaction of compound B with the substituted sulfonyl chloride in step S2 is an aprotic solvent; and / or, in step S2, the molar ratio of compound B to substituted sulfonyl chloride is 1:0.8 to 1:3; And / or, the temperature for reacting the compound B with the substituted sulfonyl chloride in step S2 is 0-25°C.

4. The method for preparing the chiral isomer of oseltamivir according to claim 1, characterized in that: In step S3, the molar ratio of compound C to tert-butylamine or allylamine is 1:0.8 to 1:5; And / or, the reaction solvent for the configuration reversal in step S3 is selected from one or more of methanol, ethanol, and isopropanol; And / or, the reaction temperature of the configuration inversion in step S3 is 55-65°C; and / or, in step S4, the compound D reacts with acetic anhydride or acetyl chloride in the presence of a catalyst, N,N-dimethylpyridine; And / or, in step S4, the compound D reacts with acetic anhydride in the presence of sodium acetate; And / or, in step S4, the compound D reacts with acetyl chloride in the presence of a weak base and an aprotic solvent; and / or, when the compound D reacts with acetic anhydride in step S4, the molar ratio of acetic anhydride to compound D is 2 to 20:1; And / or, the reaction of compound D and acetic anhydride in step S4 is heating to reflux; And / or, when the compound D reacts with acetyl chloride in step S4, the molar ratio of acetyl chloride to compound D is 1:1 to 5:

1.

5. The method for preparing the chiral isomer of oseltamivir according to claim 1, characterized in that: In step S5, the deprotection of compound E is carried out under the action of trifluoroacetic acid or ethanolic hydrogen chloride solution or methanolic hydrogen chloride solution.

6. The method for preparing the chiral isomer of oseltamivir according to claim 5, characterized in that: The concentration of the hydrogen chloride ethanol solution in step S5 is 8wt% to 12wt%; and / or, the concentration of the hydrogen chloride methanol solution in step S5 is 8wt% to 12wt%; And / or, in step S5, the molar ratio of compound E to trifluoroacetic acid or hydrogen chloride is 1:2 to 1:50; and / or, in step S5, the molar ratio of the compound E to the hydrogen chloride in the hydrogen chloride ethanol solution or the hydrogen chloride methanol solution is 1:2 to 1:50; And / or, the deprotection temperature in step S5 is 45-55°C.

7. The method for preparing the chiral isomer of oseltamivir according to claim 1, characterized in that: The positive ion capture agent in step S6 is 1,3-dimethylbarbituric acid; And / or, in step S6, the molar ratio of compound F to the positive ion capture agent is 1:1-2; And / or, the catalyst in step S6 is palladium acetate and triphenylphosphine; and / or, in step S6, the molar ratio of the catalyst to compound F is 0.5% to 5%; And / or, the reaction temperature of the compound F, the positive ion capture agent and the catalyst in step S6 is 25-35°C.

8. The method for preparing the chiral isomer of oseltamivir according to claim 1, characterized in that: The compound G obtained in step S6 is treated with an ethanol solution of hydrogen chloride to obtain its hydrochloride form, i.e., compound H, and the reaction formula is as follows:

9. The method for preparing the chiral isomer of oseltamivir according to claim 8, characterized in that: The preparation of compound H specifically includes the steps of: dissolving compound G in ethyl acetate, slowly adding ethanol solution of hydrogen chloride to adjust the solution pH to less than 5, keeping warm at -5 to 0°C for crystallization, filtering and washing to obtain compound H.

10. An intermediate compound of an oseltamivir chiral isomer prepared by the preparation method according to any one of claims 1 to 9, characterized in that: The structural formula is: Among them, R 1 is selected from one of allyl and tert-butyl; R 2 is selected from one of allyl and tert-butyl; R 4 Selected from one of allyl and tert-butyl.

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