A preparation method of oseltamivir chiral isomers

Abstract

The preparation method of the oseltamivir chiral isomer of the present invention involves ring-opening the ternary ring compound A to obtain compound B, reacting it with a substituted sulfonyl chloride under the action of an acid-binding agent to obtain compound C, obtaining the compound D with inverted configuration under the action of tert-butylamine or allylamine, then reacting it with acetic anhydride or acetyl chloride to obtain compound E, deprotecting compound E to obtain compound F, finally obtaining compound G under the catalytic action of a positive ion trapping agent and a catalyst, and treating it with an ethanol solution of hydrogen chloride to obtain the oseltamivir diastereomer H, i.e., in the form of hydrochloride; the white solid obtained after purification with an ethanol solution of hydrogen chloride and ethyl acetate is easy to store; the preparation method of the present invention avoids the introduction of azide groups, the raw materials are easily available, the reaction conditions are mild, it is safe and easy to operate, the product purity is high, and the solid is more convenient to store.

Description

Technical Field

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

[0002] Oseltamivir phosphate, English name: Oseltamivir phosphate, chemical name: (3R,4R,5S)-4-acetamido-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 annual global sales have exceeded $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 3 chiral centers in the structure of oseltamivir, 1 enantiomer and 6 diastereoisomers. Usually, oseltamivir refers to the configuration of the chiral carbon corresponding to 3R,4R,5S, and the structural formula is as follows:

[0004]

[0005] In 2017, Xinbosi Biology reported a method for preparing this isomer. As described in patent CN108047077A, the route is as follows:

[0006]

[0007] The configuration of the chiral carbon of this isomer corresponds to 3R,4R,5R. The three-membered ring compound 1 is ring-opened with sodium azide, and the configuration is inverted. Through the Staudinger reaction, it reacts with Boc anhydride to obtain compound 3. Under the action of an acid-binding agent and methanesulfonyl chloride, compound 4 is formed. Then, under the action of sodium azide, the configuration is inverted to obtain compound 5. Then, the azide group is reduced and reacted with acetic anhydride to obtain compound 6. Finally, the Boc protection is removed to obtain compound 7. However, this method uses the relatively dangerous sodium azide reagent twice, and the operation is complex. Summary of the Invention

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

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

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

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

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

[0013] S4. The compound D reacts with acetic anhydride or acetyl chloride to obtain compound E;

[0014] S5. The compound E is deprotected to obtain compound F;

[0015] S6. The compound F is obtained to obtain compound G under the action of a positive ion capturer and a catalyst;

[0016] The reaction formula is as follows:

[0017]

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

[0019] The present invention also provides an intermediate compound of an oseltamivir chiral isomer 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 or tert-butyl; R 2 is selected from one of allyl or tert-butyl; R 4 is selected from one of allyl or tert-butyl.

[0022] As described above, the preparation method of the oseltamivir chiral isomer of the present invention has the following beneficial effects:

[0023] The preparation method of the oseltamivir chiral isomer of the present invention involves ring-opening the ternary ring compound A to obtain compound B, reacting it with a substituent sulfonyl chloride to obtain compound C, obtaining the compound D with inverted configuration under the action of tert-butylamine or allylamine, then reacting it with acetic anhydride or acetyl chloride to obtain compound E, deprotecting to obtain compound F, and finally removing the allyl or tert-butyl group under the catalysis of a positive ion capturer and a catalyst to obtain the oseltamivir chiral isomer compound G; furthermore, treating it with an ethanol solution of hydrogen chloride to obtain the oseltamivir diastereoisomer H (in the form of hydrochloride), and the white solid obtained after purification with an ethanol solution of hydrogen chloride and ethyl acetate is easy to store; the preparation method of the present invention avoids the introduction of azide groups, the reaction raw materials are easily available, the reaction conditions are mild, and it is safe and easy to operate.

[0024] The present invention provides a simple and clear synthesis method, with safe and easy process operation, high product purity, and more convenient solid storage. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

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

[0031] Figure 7 It is the carbon spectrum of compound 8 of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0032] The following specific examples illustrate the embodiments of the present invention. Those skilled in the art can easily understand the other advantages and effects of the present invention from the content disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, and various details in this specification can also be modified or changed 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 only schematically illustrate the basic concept of the present invention. Therefore, only the components related to the present invention are shown in the drawings, rather than being drawn according to the number, shape, and size of the components in actual implementation. The type, quantity, and proportion of each component in actual implementation can be arbitrarily changed, and the component layout type may also be more complex.

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

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

[0036] S2. Reacting the compound B with a substituent sulfonyl chloride to obtain compound C;

[0037] S3. Performing a configuration inversion on the compound C 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. Obtaining compound G from the compound F under the action of a positive ion capturer and a catalyst;

[0041] The reaction formula is as follows:

[0042]

[0043] Wherein, R 1 is selected from one of allyl or tert-butyl; R 2 is selected from one of allyl or tert-butyl; R 3 is selected from one of methyl, ethyl, phenyl, or p-tolyl; R 4 is selected from one of allyl or 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 dosage of magnesium chloride to compound A is 1.1 - 2.0:1. For example, it is 1.1 - 1.2:1, 1.2 - 1.4:1, 1.4 - 1.5:1, 1.5 - 1.6:1, 1.6 - 1.8:1, or 1.8 - 2.0:1. In a preferred embodiment of the present invention, the molar ratio of the dosage of magnesium chloride to compound A is 1.4 - 1.5:1.

[0046] The solvent for the ring-opening reaction described 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] The secondary amine described in step S1 is selected from one of 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, it can be 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, it can be 45 - 50 °C or 50 - 55 °C.

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

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

[0052] The reaction of compound B with the substituent sulfonyl chloride in step S2 is carried out under the action of an acid-binding agent.

[0053] Among them, 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 substituent sulfonyl chloride is 1 - 3:1. For example, it can be 1 - 1.3:1, 1.3 - 1.5:1, 1.5 - 1.8:1, 1.8 - 2:1, 2 - 2.3:1, 2.3 - 2.5:1, 2.5 - 2.8:1, or 2.8 - 3:1. In a preferred embodiment of the present invention, the molar ratio of the amount of the acid-binding agent to the substituent sulfonyl chloride is 1.3:1.

[0055] The solvent for the reaction of compound B with the substituent 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 the substituent sulfonyl chloride in step S2 is 1:0.8 to 1:3. For example, it is 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 the substituent sulfonyl chloride is 1:1.5.

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

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

[0059] In the preparation method of the present invention, the molar ratio of compound C to tert-butylamine or allylamine in step S3 is 1:0.8 to 1:5. For example, it is 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 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 for the configuration inversion in step S3 is 55 to 65 °C. For example, it is 55 to 60 °C or 60 to 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 the configuration-inverted compound (3R,4R,5R)-D. After the reaction is completed, the product C can be obtained directly by concentrating under reduced pressure.

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

[0064] Among them, the molar ratio of compound D to N,N-dimethylpyridine is 1:0.01 to 1:1. For example, it is 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 compound D to N,N-dimethylpyridine is 1:0.005.

[0065] In step S4, compound D reacts with acetic anhydride in the presence of sodium acetate. The molar ratio of compound D to sodium acetate is 1:1 - 1:2. For example, it is 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 compound D to sodium acetate is 1:1.06.

[0066] When 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, it is 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 with acetic anhydride in step S4 is heated to reflux. The specific temperature is 135 to 145 °C. For example, it is 135 to 137 °C, 137 to 139 °C, 139 to 141 °C, 141 to 143 °C, or 143 to 145 °C.

[0068] In step S4, 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] The reaction temperature of compound D and acetyl chloride in step S4 is heated to the reflux state according to the selected solvent.

[0070] When 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, it is 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 as follows: Compound D and acetic anhydride (both a solvent and a reactant) under the action of sodium acetate, with 4-N,N-dimethylpyridine (DMAP) as a catalyst, are refluxed and stirred to obtain the acetyl-protected compound (3R,4R,5R)-E. After the reaction is completed, it is concentrated, the pH is adjusted to >8 with sodium hydroxide solution, the optimal pH = 9 - 12, and it is extracted with an organic solvent and then concentrated 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 hydrochloric acid ethanol solution or hydrochloric acid methanol solution. In a preferred embodiment of the present invention, the deprotection of compound E is carried out under the action of trifluoroacetic acid.

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

[0074] The concentration of the hydrochloric acid methanol solution is 8wt% - 12wt%. For example, it is 8wt% - 9wt%, 9wt% - 10wt%, 10wt% - 11wt%, or 11wt% - 12wt%. In a preferred embodiment of the present invention, the concentration of the hydrochloric acid methanol solution is 10%. Specifically, it is prepared by dissolving 1 g of hydrogen chloride in 9 g of methanol.

[0075] In step S5, the molar ratio of compound E to trifluoroacetic acid is 1:2 to 1:50. For example, it is 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] In step S5, the molar ratio of compound E to hydrogen chloride in hydrogen chloride ethanol solution or hydrogen chloride methanol solution is 1:2 to 1:50. For example, it is 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 hydrogen chloride ethanol solution or hydrogen chloride methanol solution is 1:10 to 1:15.

[0077] In step S5, the deprotection temperature is 45 to 55 °C. For example, it is 45 to 50 °C or 50 to 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, it is concentrated, the pH is adjusted to >8 with sodium hydroxide solution, the optimal pH = 10 to 14, and the product F can be obtained after concentration by toluene extraction.

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

[0080] In step S6, the molar ratio of compound F to the positive ion capturer is 1:1 to 2. For example, it is 1:1 to 1.2, 1:1.2 to 1.4, 1:1.4 to 1.6, 1:1.6 to 1.8 or 1:1.8 to 2.

[0081] In step S6, the catalyst is palladium acetate and triphenylphosphine.

[0082] Among them, the molar ratio of palladium acetate to triphenylphosphine is 1:1 to 1:10. For example, it is 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] The molar ratio of the catalyst to compound F described in step S6 is 0.5% to 5%. For example, it is 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 compound F with the positive ion scavenger and the catalyst in step S6 is 25 to 35 °C. For example, it is 25 to 30 °C or 30 to 35 °C.

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

[0086]

[0087] Specifically, the preparation of compound H includes the steps of: dissolving compound G in ethyl acetate, slowly adding an ethanol solution of hydrogen chloride to adjust the solution pH < 5, carrying out crystallization while maintaining the temperature at -5 to 0 °C, filtering and washing to obtain compound H.

[0088] The ratio of compound G to ethyl acetate is 1 g : (2 - 4) mL. For example, it is 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 removes the allyl group under the catalysis of 1,3 - dimethylbarbituric acid (NDMBA) as the positive ion scavenger, palladium acetate and triphenylphosphine to obtain the crude product compound G. After the reaction is completed, it is concentrated under reduced pressure, dissolved by adding ethyl acetate (2 - 4 times the mass - volume), and the pH is adjusted to < 5 with an ethanol solution of hydrogen chloride, with the optimal pH = 1 - 2. Crystallization is carried out with stirring at -5 to 0 °C, and the white solid product H can be obtained by filtration, with a purity of over 96%.

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

[0092]

[0093] Wherein, R 1 is selected from one of allyl or tert - butyl; R 2 is selected from one of allyl or tert - butyl; R 4 is selected from one of allyl or 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, protected by nitrogen, stirred at room temperature, and diallylamine (38.20 g, 0.39 mol) was added dropwise. The addition was completed in 5 - 10 min. The reaction solution was heated to 50 °C and reacted for 4 hours, then cooled to 0 - 5 °C, and the pH was adjusted to 1 - 2 by dropwise addition of 1 mol / L hydrochloric acid. After liquid separation, the aqueous phase was adjusted to pH = 13 - 14 with 10% sodium hydroxide solution, and extracted twice with 100 ml of ethyl acetate. The organic phases were combined, dried over 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), protected by nitrogen, stirred at 0 - 5 °C, and methanesulfonyl chloride (8.55 g, 74.7 mmol) and triethylamine (8.62 g, 85.4 mmol) were added dropwise in sequence, controlling the internal temperature below 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, stirred, and liquid-separated. The organic phase was dried over sodium sulfate, filtered, concentrated under reduced pressure, and separated by column chromatography to obtain 15.03 g of a light yellow liquid compound 3 (3R,4S,5R) 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 successively added to CH3OH (150 ml), protected by nitrogen, heated to 60 °C and stirred for 2 hours while maintaining the temperature. After concentration under reduced pressure, separation by column chromatography gave 13.1 g of a 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 successively added to Ac2O (35.12 g, 340 mmol). Under nitrogen protection, the temperature was raised to reflux and stirred for 12 hours. After cooling to 0 - 5 °C, 10% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 9 - 10. It was extracted with ethyl acetate (50 ml), dried over sodium sulfate, filtered, concentrated under reduced pressure, and then 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 1H-NMR (400 Mz, CDCl3): δ 6.90 (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 13C-NMR (400 Mz, CDCl3): δ 172.8, 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). Under nitrogen insulation, the temperature was raised to 50 °C and stirred for 2 hours. After concentration under reduced pressure, 10% sodium hydroxide solution was used to adjust the pH to 13 - 14. It was extracted twice with toluene (20 ml), washed with saturated sodium chloride solution (10 ml), dried over sodium sulfate, concentrated under reduced pressure, and then separated by column chromatography to obtain 4.02 g of yellow oily liquid compound 6 (3R, 4R, 5R) with a purity of 98% and a yield of 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 successively added to ethanol (25 ml). Under nitrogen protection, the temperature was raised to 30 °C and stirred for 2 hours. After concentration under reduced pressure, the crude product compound 7 (3R, 4R, 5R) was obtained. Ethyl acetate (10 ml) was added, and the pH was adjusted to 1 - 2 by dropping hydrochloric acid ethanol solution, and stirred at 0 °C for 1 - 2 hours. After filtration and washing with a small amount of ethyl acetate, 1.15 g of white solid (compound 8) with a purity of 96% and a two-step yield of 33% was obtained. [M + 1] + 313.1617.

[0107] 1 H-NMR(400Mz,d 6 -DMSO): δ8.40(d, J = 8.0Hz, 1H), 8.31(brs, 3H, active hydrogen), 6.71(s, 1H), 4.41(d, J = 7.6Hz, 1H), 4.17 - 4.04(m, 3H), 3.48 - 3.42(m, 1H), 3.21 - 3.17(m, 1H), 2.60(dd, J = 5.2Hz, 17.6Hz, 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 = 7.2Hz, 3H), 0.85(dt, J = 7.2Hz, 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, protected by nitrogen, stirred at room temperature, and diallylamine (55.00 g, 0.56 mol) was added dropwise. The addition was completed in 5 - 10 min. The reaction solution was heated to 50 °C and reacted for 4 hours. Then it was cooled to 0 - 5 °C, and 1 mol / L hydrochloric acid was added dropwise to adjust the pH to 1 - 2. After liquid separation, the aqueous phase was adjusted to pH = 13 - 14 with 10% sodium hydroxide solution, and extracted twice with 100 ml of ethyl acetate. The organic phases were combined, dried over 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), protected by nitrogen, stirred at 0 - 5 °C, and methanesulfonyl chloride (27.50 g, 0.24 mmol) and triethylamine (32.30 g, 0.32 mmol) were added dropwise in sequence, controlling the internal temperature below 10 °C. After the addition was completed, it was slowly heated to 25 °C and stirred for 1 h. Water (100 ml) was added, stirred, and liquid-separated. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 83.40 g of compound 3 for direct use in the next step of the reaction.

[0114] Compound 3 (83.40 g) and tert-butylamine (23.60 g, 0.32 mol) were added to CH3OH (250 ml) in sequence, protected by nitrogen, refluxed and stirred for 2 hours, and concentrated under reduced pressure to obtain 63.01 g of compound 4 for direct use in the next step of the 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 and stirred for 12 hours. After concentration under reduced pressure, it was cooled to 0 - 5 °C, and 10% aqueous sodium hydroxide solution was added dropwise to adjust the pH to 9 - 10. It was extracted with ethyl acetate (200 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain 53.91 g of a yellow oily liquid compound 5 with a yield of 75% for the three-step reaction in total.

[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, and concentrated under reduced pressure. The pH was adjusted to 13 to 14 with 10% sodium hydroxide solution, stirred for 10 minutes, and then retested. The solution was 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 under nitrogen protection. The temperature was raised to 30°C and stirred for 2 hours. After concentration under reduced pressure, ethyl acetate (80 ml) was added and ethanolic hydrogen chloride solution was added 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 >96%.

[0120]

[0121] In summary, the preparation method of the chiral isomer of oseltamivir of the present invention is to open the ring of 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 binder to obtain compound C, react with tert-butylamine or allylamine to obtain compound D with inverted configuration, and then react with acetic anhydride or acetyl chloride to obtain compound E, remove the tert-butyl protection by trifluoroacetic acid to obtain compound F, and finally remove the allyl group under the catalysis of 1,3-dimethylbarbituric acid (NDMBA) as a positive ion trap and palladium acetate and triphenylphosphine, and treat with an ethanolic solution of hydrogen chloride to obtain oseltamivir diastereomer H (hydrochloride form); after purification by an ethanolic solution of hydrogen chloride and ethyl acetate, the obtained white solid is easy to store and can be better used for oseltamivir product quality control. Therefore, the present invention effectively overcomes the various shortcomings of the prior art and has 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 skilled in 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 one of ordinary skill in the art without departing from the spirit and technical principles disclosed herein are intended to be covered by the claims of the present invention.

Claims

1. A preparation method of oseltamivir chiral isomers, characterized in that, It includes the following steps: S1. The ternary ring compound A undergoes a ring-opening reaction with a secondary amine to obtain compound B; S2. The compound B reacts with a substituent sulfonyl chloride to obtain compound C; S3. The compound C undergoes a configuration inversion under the action of tert-butylamine or allylamine to obtain compound D; S4. The compound D reacts with acetic anhydride or acetyl chloride to obtain compound E; S5. The compound E is deprotected to obtain compound F; S6. The compound F is obtained under the action of a positive ion trapping agent and a catalyst to obtain compound G; The reaction formula is as follows: Among them, R 1 is selected from one of allyl or tert-butyl; R 2 is selected from one of allyl or tert-butyl; R 3 is selected from one of methyl, ethyl, phenyl, or p-tolyl; R 4 is selected from one of allyl or tert-butyl; In step S1, the secondary amine is selected from one of diallylamine, di-tert-butylamine or tert-butyl allylamine; In step S2, the substituent sulfonyl chloride is selected from one of methanesulfonyl chloride, ethylsulfonyl chloride, phenylsulfonyl chloride, p-toluenesulfonyl chloride; In step S6, the positive ion trapping agent is 1,3-dimethylbarbituric acid; In step S6, the catalyst is palladium acetate and triphenylphosphine.

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

3. The preparation method of the oseltamivir chiral isomer according to claim 1, characterized in that In step S2, the reaction of the compound B with the substituent sulfonyl chloride is carried out under the action of an acid-binding agent; And / or, in step S2, the solvent for the reaction of the compound B with the substituent sulfonyl chloride is an aprotic solvent; And / or, in step S2, the molar ratio of the compound B to the substituent sulfonyl chloride is 1:0.8 - 1:3; And / or, in step S2, the temperature of the reaction of the compound B with the substituent sulfonyl chloride is 0 - 25 °C.

4. The preparation method of the oseltamivir chiral isomer according to claim 1, characterized in that, In step S3, the molar ratio of the compound C to tert-butylamine or allylamine is 1:0.8 - 1:5; And / or, in step S3, the reaction solvent for the configuration inversion is selected from one or more of methanol, ethanol, isopropanol; And / or, in step S3, the reaction temperature for the configuration inversion is 55 - 65 °C; And / or, in step S4, the compound D reacts with acetic anhydride or acetyl chloride under the action 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 the compound D is 2 - 20:1; And / or, the reaction of the compound D with acetic anhydride in step S4 is heated to reflux; And / or, when the compound D reacts with acetyl chloride in step S4, the molar ratio of acetyl chloride to the compound D is 1:1 - 5:

1.

5. The preparation method of the oseltamivir chiral isomer according to claim 1, characterized in that, In step S5, the deprotection of the compound E is carried out under the action of trifluoroacetic acid or a hydrogen chloride ethanol solution or a hydrogen chloride methanol solution.

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

7. The preparation method of the oseltamivir chiral isomer according to claim 1, characterized in that, The molar ratio of compound F to the positive ion scavenger described in step S6 is 1:1 to 2; And / or, the molar ratio of the catalyst to compound F described in step S6 is 0.5% to 5%; And / or, the reaction temperature of compound F with the positive ion scavenger and the catalyst described in step S6 is 25 to 35 °C.

8. The preparation method of the oseltamivir chiral isomer according to claim 1, characterized in that, The compound G prepared 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 preparation method of the oseltamivir chiral isomer according to claim 8, wherein The preparation of compound H specifically includes the steps of: dissolving compound G in ethyl acetate, slowly adding an ethanol solution of hydrogen chloride to adjust the solution pH < 5, Crystallizing at -5 to 0 °C, filtering and washing to obtain compound H.

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