Process for the preparation of oseltamivir and its phosphate and intermediates thereof

Abstract

The application belongs to the technical field of pharmaceutical chemistry synthesis, and specifically discloses a preparation method of oseltamivir and a phosphate thereof and an intermediate thereof, which comprises the following steps: (1) a compound of formula VII is reacted with VIII under the action of a base in a solvent to obtain an intermediate of formula VI, and then the intermediate of formula VI is reacted under the action of a strong base at high temperature to obtain formula V; (2) formula V is subjected to ring-opening reaction with tert-butylamine in a solvent under the catalysis of a Lewis acid to obtain formula IV; (3) formula IV is reacted with an acetylating agent in a solvent under the action of a base to obtain formula III; (4) formula III is reacted under the action of an acid at a certain temperature to obtain formula II; and (5) formula II is subjected to salt formation with phosphoric acid in a solvent to obtain oseltamivir. The preparation method has the characteristics of simple operation, low cost, high yield, high optical purity of the product, stable process and the like, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of oseltamivir and its phosphate and an intermediate thereof. BACKGROUND

[0002] Oseltamivir phosphate (trade name: Tamiflu) is the phosphate of oseltamivir, and its chemical name is (3R, 4R, 5S)-4-acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene carboxylate phosphate, which is an effective anti-influenza virus drug. It can inhibit the neuraminidase on the surface of influenza A and B viruses, prevent newly replicated virus particles from being released from human cells, and make the life cycle of the virus difficult to continue.

[0003] Oseltamivir phosphate is developed by Gilead Company and jointly developed by Roche, and is sold by Roche. It was approved for marketing in Switzerland in 1999, and was approved by the FDA in the United States in the same year. It is recognized as the most effective drug against influenza, so its synthesis and industrialization are of great significance.

[0004] The synthetic route jointly developed by Gilead Company and Roche mainly uses shikimic acid as a starting material, and its preparation route is as follows. The whole route starts from shikimic acid, and is subjected to esterification, ketal protection, methanesulfonylation, ketal exchange, selective reduction, intramolecular cyclization, azide ring opening of the epoxy intermediate II, generation of aziridine, again azide ring opening, amino acetylation, azide reduction and salt formation, to obtain oseltamivir phosphate, with a total yield of 17.7%. The yield is low, and dangerous chemicals such as sodium azide, trimethyl phosphorus (flammable and explosive), trifluoromethanesulfonic acid (expensive), methylsulfonyl chloride and the like are used. In particular, sodium azide is highly toxic and explosive, so that there are great hidden dangers in industrial production.

[0005]

[0006] After that, Roche Company improved the above route starting from the epoxy intermediate II in order to avoid the use of sodium azide, and specifically proposed two improved routes: in the improved route 1, allylamine is used to open the ring of the epoxy intermediate II, and from shikimic acid to oseltamivir phosphate, it takes 17 steps with a yield of 22.3%, and from the epoxy intermediate II to oseltamivir phosphate, the yield is 35-38%, the entire route uses expensive palladium catalyst twice and Pd / C catalytic deallylation twice to prepare oseltamivir, which is high in cost (see patent US6403824, J. Org. Chem. 2001, 66, 2044.); in the improved route 2, tert-butylamine is used to open the ring of the epoxy intermediate II, and then diallylamine is used to open the ring of the aziridine compound, and from shikimic acid to oseltamivir phosphate, it takes 14 steps with a yield of 39.4%, which also needs to use expensive palladium catalyst, is high in cost, and is relatively complicated (see Org. Process Res. Dev. 2004, 8, 86.).

[0007] Based on the prior art, in the synthesis of oseltamivir and its phosphate, the use of dangerous reagent sodium azide and expensive noble metal catalyst is avoided, and the present application is proposed. SUMMARY

[0008] In order to solve the problems of using dangerous reagent sodium azide and expensive noble metal catalyst, and many reaction steps, low total yield and high cost in the known synthesis methods of oseltamivir and its phosphate, the present application provides a new synthesis method of oseltamivir and its phosphate, which has the advantages of good stereoselectivity, short route, mild reaction conditions, low cost and high industrial feasibility.

[0009] One object of the present application is to provide a synthesis method of oseltamivir, which specifically comprises the following steps:

[0010] Step (1) the compound of formula VII reacts with VIII in a solvent under the action of base 1 to obtain the intermediate of formula VI, and then the intermediate of formula VI reacts under the action of base 2 at a certain reaction temperature to obtain formula V:

[0011]

[0012] (2) formula V undergoes ring-opening reaction with tert-butylamine in a solvent under the catalysis of Lewis acid to obtain formula IV:

[0013]

[0014] (3) formula IV reacts with acetylating agent in a solvent under the action of base to obtain formula III:

[0015]

[0016] (4) Formula III is prepared by reacting Formula III under the action of an acid at a certain temperature to obtain oseltamivir Formula II:

[0017]

[0018] In some preferred embodiments, the base 2 in step (1) above is selected from sodium hydride.

[0019] In some embodiments, in step (1) above, the solvent is selected from one or a combination of two or more of toluene, xylene, mesitylene, dioxane, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide; preferably, in step (1), the solvent is dioxane.

[0020] In some embodiments, in step (1) above, the base 1 is selected from one or a combination of two or more of triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, triethylenediamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide; preferably, in step (1), the base 1 is selected from triethylamine.

[0021] In some embodiments, the reaction temperature in step (1) above refers to 50-200°C, preferably 60-100°C; more preferably 80°C.

[0022] In some embodiments, in step (1) above, the molar ratio of base 1 to Formula VII compound is (3-5): 1, preferably 3: 1.

[0023] In some embodiments, in step (2) above, the Lewis acid is selected from one or a combination of two or more of aluminum chloride, iron trichloride, zinc chloride, magnesium chloride, magnesium bromide, manganese chloride, nickel chloride, boron trifluoride etherate, p-toluenesulfonic acid, trifluoromethanesulfonic acid; preferably, in step (2), the Lewis acid is magnesium chloride or magnesium bromide.

[0024] In some embodiments, in step (2) above, the solvent is selected from one or a combination of two or more of toluene, xylene, mesitylene, dioxane, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide; preferably, in step (2), the solvent is toluene.

[0025] In some embodiments, in step (3) above, the acetylating agent is selected from acetyl chloride or acetic anhydride, preferably acetic anhydride.

[0026] In some embodiments, the base in step (3) above is selected from one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, triethylenediamine, 1,8-diazabicycloundec-7-ene, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, sodium ethoxide; preferably, the base in step (3) is triethylamine.

[0027] In some embodiments, the solvent in step (3) above is selected from one or a combination of two or more of toluene, xylene, mesitylene, dioxane, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide; preferably, the solvent in step (3) is dichloromethane.

[0028] In some embodiments, the acid in step (4) above is selected from hydrogen chloride ethanol solution, hydrogen chloride methanol solution, hydrogen chloride dioxane solution, hydrogen chloride ethyl acetate solution, trifluoroacetic acid, and a combination thereof, preferably trifluoroacetic acid.

[0029] In some embodiments, the temperature in step (4) above is 0-100 °C; preferably 50-100 °C, more preferably 60-70 °C.

[0030] In some preferred embodiments, the present application provides a method for synthesizing oseltamivir, which specifically comprises the following steps:

[0031] Step (1) dissolving the compound of formula VII in dioxane, adding triethylamine, adding dropwise a dioxane solution of formula VIII, after the addition, warming to 15-30 °C for reaction, after the reaction is completed, quenching with ice water, extracting with dichloromethane, taking the organic layer and concentrating under reduced pressure to obtain the intermediate of formula VI; dissolving the intermediate of formula VI in dioxane, adding sodium hydride, warming to 60-100 °C for reaction, after the reaction is completed, extracting with dichloromethane, taking the organic layer and concentrating under reduced pressure to obtain the intermediate of formula V;

[0032] Step (2) first mixing Lewis acid, toluene and tert-butylamine to obtain a Lewis acid-tert-butylamine complex, then dissolving the intermediate of formula V in toluene, adding the Lewis acid-tert-butylamine complex, warming to 55-65 °C for reaction, after the reaction is completed, extracting with dichloromethane, taking the organic phase and concentrating under reduced pressure to obtain the intermediate of formula IV;

[0033] Step (3) mixing the intermediate of formula IV, triethylamine, dichloromethane and acetic anhydride, reacting under N2 protection, after the reaction is completed at 15-30 °C, extracting with dichloromethane, taking the organic phase and concentrating under reduced pressure to obtain the intermediate of formula III;

[0034] Step (4) mixing the intermediate of formula III and trifluoroacetic acid, and reacting at 60-70℃, after the reaction is completed, adding water, adjusting the pH to 7-8 by dropwise adding a base, extracting with dichloromethane, and taking the organic phase to concentrate under reduced pressure to obtain oseltamivir (formula II).

[0035] In some more preferred embodiments, the present application provides a method for synthesizing oseltamivir, specifically comprising the following steps:

[0036] Step (1) mixing chlorosulfonyl isocyanate and dioxane, dropwise adding a solution of t-butyl alcohol in dioxane, and reacting at 0-10℃ for 1h to prepare a dioxane solution of formula VIII; dissolving the compound of formula VII in dioxane, adding triethylamine, and dropwise adding the prepared dioxane solution of formula VIII; after the addition is completed, warming to 25℃ to react, after the reaction is completed, quenching with ice water, extracting with dichloromethane, taking the organic layer to concentrate under reduced pressure to obtain the intermediate of formula VI; dissolving the intermediate of formula VI in dioxane, adding sodium hydride, and warming to 80℃ under N2 protection to react, after the reaction is completed, extracting with dichloromethane, taking the organic layer to concentrate under reduced pressure to obtain the crude product of the intermediate of formula V, and further recrystallizing with ethyl acetate / n-heptane to obtain the fine product of the intermediate of formula V;

[0037] Step (2) mixing a Lewis acid, toluene and t-butylamine, and reacting at 15-25℃ for 6h to obtain a Lewis acid-t-butylamine complex; dissolving the intermediate of formula V in toluene, adding the Lewis acid-t-butylamine complex, and warming to 55-65℃ to react, after the reaction is completed, extracting with dichloromethane, taking the organic phase to concentrate under reduced pressure to obtain the crude product of the intermediate of formula IV, and further recrystallizing with ethyl acetate / n-heptane to obtain the fine product of the intermediate of formula IV; the Lewis acid is selected from magnesium chloride or magnesium bromide.

[0038] Step (3) mixing the intermediate of formula IV, triethylamine, dichloromethane and acetic anhydride, and reacting under N2 protection, after the reaction is completed at 15-30℃, quenching with water, extracting with dichloromethane, and taking the organic phase to concentrate under reduced pressure to obtain the intermediate of formula III;

[0039] Step (4) mixing the intermediate of formula III and trifluoroacetic acid, and reacting at 60±70℃, after the reaction is completed, adding water, adjusting the pH to 7-8 by dropwise adding sodium hydroxide, extracting with dichloromethane, taking the organic phase to concentrate under reduced pressure to obtain the crude product of oseltamivir, and further obtaining the fine product of oseltamivir by ethyl acetate and n-heptane.

[0040] Another object of the present application is to provide a method for synthesizing oseltamivir phosphate, comprising the following steps:

[0041] Step (5) preparing oseltamivir (formula II) according to any of the above methods, and forming a salt with phosphoric acid in a solvent to obtain oseltamivir phosphate (formula I)

[0042] wherein:

[0043] The solvent is selected from methanol, anhydrous ethanol or propanol, preferably anhydrous ethanol; the phosphoric acid is selected from 85% phosphoric acid; the temperature of the salt formation reaction is 60-70°C; the step (5) further comprises cooling and crystallization after the salt formation with phosphoric acid, the cooling temperature is -5-5°C, and the cooling and crystallization time is 2h.

[0044] In some embodiments, the above step (5) is specifically as follows: 85% phosphoric acid and anhydrous ethanol are stirred and mixed, an ethanol solution of oseltamivir (formula II) is added dropwise, and the reaction is carried out at 60-70°C; after the reaction is completed, the temperature is lowered to -5-5°C, and stirring and crystallization are carried out for 2h to obtain oseltamivir phosphate.

[0045] Any of the above embodiments can be arbitrarily combined to form a new technical solution.

[0046] Another object of the present application is to provide an intermediate compound of oseltamivir, which is selected from:

[0047]

[0048] The present application provides a synthesis route as follows:

[0049]

[0050] The present application is finally proposed after a large amount of creative labor, first, the strong leaving property of the triethylammonium group in the compound of formula VIII is utilized, and the hydroxyl group of the compound of formula VII undergoes a substitution reaction under the action of a base; then the hydrogen at the sulfonamide position of the compound of formula VI is removed by a strong base, and a trans nucleophilic attack is carried out on the methyl sulfonate to form the compound of formula V; the sulfonate group undergoes a trans nucleophilic reaction with the tertiary butylamine nucleophile under the catalysis of a Lewis acid to obtain the compound of formula IV with high stereoselectivity; and the compound of formula IV is then acetylated and deprotected to obtain oseltamivir.

[0051] The key point of the present application is that after obtaining the compound of formula VI, a reaction needs to be carried out under strong base conditions, and the strong basicity is conducive to the reaction; no base or weak basicity may cause an elimination reaction, and it is difficult to obtain the compound of formula V; the present inventors have found in research that when sodium hydride is used as the strong base, the compound of formula V can be obtained in a high yield and with high stereoselectivity, while the yield of the compound of formula V obtained by using other bases such as triethylamine is very low.

[0052] The present application has the following beneficial effects:

[0053] 1. A new method for synthesizing oseltamivir and its phosphate salt is provided, which utilizes the construction of a sulfonate five-membered ring and a trans nucleophilic attack to construct a key chiral intermediate, and the stereoselectivity is good and the isomer impurities are few;

[0054] 2. The introduction of the two nitrogen-containing functional groups in the product structure of this invention avoids the use of the hazardous chemical sodium azide. Instead, one nitrogen atom is introduced by first substituting and then cyclizing with Burgess reagent VIII, and then the ring is opened under the action of tert-butylamine to introduce the other nitrogen atom. The synthetic route does not require the use of expensive raw materials, has low cost, and simple process route.

[0055] 3. This invention has the advantages of short route, mild reaction conditions, low cost, and high industrial feasibility. Detailed Implementation

[0056] The present invention will be further described in detail below with reference to the embodiments, but this is not intended to limit the present invention. Any equivalent substitutions made in the art based on the disclosure of the present invention shall fall within the protection scope of the present invention.

[0057] The raw materials and reagents used in this invention can all be purchased commercially.

[0058] Nuclear magnetic resonance (NMR) 1 HNMR shift (δ) is given in parts per million (ppm); nuclear magnetic resonance (NMR) 1 The ¹H NMR (hydrocarbon NMR) measurements were performed using a Bruker Avance-300 NMR spectrometer. The solvent was deuterated chloroform (CDCl³⁻d), and the internal standard was tetramethylsilane (TMS). Chemical shifts were expressed in terms of 10⁻¹⁰ NMR values. -6 (ppm) is given as the unit.

[0059] The room temperature mentioned in this invention refers to 15–30°C.

[0060] Example 1: Preparation of Compound V

[0061]

[0062] Add 6g of chlorosulfonyl isocyanate and 18ml of dioxane to a 250ml three-necked flask, and stir at room temperature under N2 protection. Slowly add a dioxane solution of tert-butanol (33g of tert-butanol dissolved in 33ml of dioxane) to the reaction system, controlling the addition temperature to ≤10℃. After the addition is complete, react at 0-10℃ for 1h to obtain a dioxane solution of compound VIII.

[0063] In a 500 ml three-necked flask, 10 g of VII, 100 ml of dioxane, stirring solution, then add 8.7 g of triethylamine, control temperature 5±5℃ stirring 30 min, the prepared compound VIII dioxane solution is slowly added to the reaction system, during the dropwise addition, control the dropwise addition temperature ≤10℃, after the dropwise addition, the temperature is raised to 25℃, and the reaction is carried out, until the raw material is consumed, the reaction is quenched by adding ice water to the reaction system, extracted with dichloromethane 3 times (50 ml*3), the organic phase is washed with 50 ml of saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 14.51 g of crude product (i.e. compound VI) dissolved in 150 ml of dioxane, 1.32 g of sodium hydride is added, N2 protection, the temperature is raised to 80℃, and the reaction is carried out, until the raw material is consumed, the reaction is cooled to room temperature, 50 ml of water and 50 ml of dichloromethane are added to the reaction system, the liquid is separated, the aqueous phase is washed with dichloromethane twice, the organic phases are combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain the crude product (i.e. compound V), which is recrystallized with ethyl acetate / n-heptane to obtain white solid (compound formula V) 8.5 g, two-step yield 69%, purity 98%.

[0064] Compound VI: 1 H NMR (400 MHz, CDC13-d) δ 6.78-6.77 (m, 1H), 5.10-5.04 (m, 1H), 4.88-4.86 (m, 1H), 4.44 (dd, 1H), 4.14 (q, 2H), 3.54-3.44 (m, 1H), 3.07 (s, 3H), 3.04-2.98 (m, 1H), 2.55-2.48 (m, 1H), 1.62-1.51 (m, 4H), 1.42 (s, 9H), 1.24 (t, 3H), 0.90 (t, 3H), 0.81 (t, 3H); MS m / z 530.2 ([M+H] + )

[0065] Compound V: 1 H NMR (400 MHz, CDC13-d) δ 6.77-6.74 (m, 1H), 5.80-5.76 (m, 1H), 4.02-3.99 (m, 1H), 3.94-3.90 (m, 1H), 4.13 (q, 2H), 3.48-3.44 (m, 1H), 3.01-2.97 (m, 1H), 2.56-2.52 (m, 1H), 1.62-1.54 (m, 4H), 1.42 (s, 9H), 1.23 (t, 3H), 0.91 (t, 3H), 0.83 (t, 3H); 13C NMR (101 MHz, CDCI3-d) δ 171.21, 165.65, 135.01, 129.33, 82.45, 81.02, 79.21, 61.37, 60.10, 57.92, 53.16, 31.22, 29.37, 26.42, 26.22, 21.03, 14.19, 9.63, 9.47; MS m / z 433.3 ([M+H] + )

[0066] Preparation of compound IV of example 2

[0067]

[0068] Into a 100ml flask, 2.2g MgCI2and 10ml toluene were added, and the mixture was dispersed under nitrogen protection and stirred at room temperature, then 7.5g tert-butylamine was added, and the reaction was carried out at room temperature for 6h to obtain a magnesium chloride-tert-butylamine complex.

[0069] Into a 250ml flask, 10.1g of compound V and 50ml of toluene were weighed, and the mixture was dissolved under nitrogen protection and stirring, then the magnesium chloride-tert-butylamine complex solution was added, and the reaction was carried out at 60±5°C until the raw material was consumed, then the reaction system was cooled to room temperature, 50ml of water was added, and the mixture was allowed to stand and separate, then the water phase was washed with dichloromethane twice (50ml*2), the organic phases were combined, and concentrated under reduced pressure to obtain a crude product which was recrystallized with ethyl acetate / n-hexane to obtain 7.6g of product (compound IV) with a yield of 81% and a purity of 98%.

[0070] Compound IV: 1 H NMR (400 MHz, CDCI3-d) δ 6.76-6.74 (m, 1H), 4.12 (q, 2H), 3.80-3.76 (m, 2H), 3.64-3.62 (m, 1H), 3.48-3.44 (m, 1H), 3.00-2.98 (m, 1H), 2.54-2.50 (m, 1H), 1.62-1.54 (m, 4H), 1.42 (s, 9H), 1.24 (s, 9H), 1.21 (t, 3H), 0.91 (t, 3H), 0.83 (t, 3H); 13 C NMR (101 MHz, CDCI3-d) δ 171.20, 165.69, 135.01, 129.35, 82.25, 81.02, 79.21, 61.17, 58.90, 57.82, 29.36, 26.43, 26.22, 21.03, 14.18, 9.65, 9.45; MS m / z 507.4 ([M+H] + )

[0071] Example 3 Preparation of Compound IV

[0072]

[0073] 4.4 g of magnesium bromide and 10 ml of toluene were added to a 100 ml three-necked flask. Under nitrogen protection, the mixture was stirred and dispersed at room temperature. Then, 7.5 g of tert-butylamine was added, and the mixture was reacted at room temperature for 6 h to obtain the magnesium bromide-tert-butylamine complex.

[0074] 10.1 g of compound V and 50 ml of toluene were weighed into a 250 ml three-necked flask. Under nitrogen protection, stirring was started to dissolve the mixture. A magnesium bromide-tert-butylamine complex solution was added, and the mixture was heated to 60 ± 5 °C. After the raw materials were consumed, the mixture was cooled to room temperature. 50 ml of water was added to the reaction system, and the mixture was allowed to stand and separate. The aqueous phase was washed twice with dichloromethane (50 ml * 2). The organic phases were combined and concentrated under reduced pressure. The crude product was recrystallized from ethyl acetate / n-hexane to obtain 7.9 g of product, with a yield of 84% and a purity of 98%. The NMR and mass spectrometry results were consistent with those of Example 2.

[0075] Example 4 Preparation of Compound III

[0076]

[0077] 9 g of compound IV, 90 ml of DCM (dichloromethane), 3.4 g of acetic anhydride, and 4.5 g of triethylamine were added sequentially to a 250 ml single-necked flask. The mixture was kept under N2 protection and reacted at room temperature. After the starting materials were consumed, 90 ml of water was added to terminate the reaction. The aqueous phase was extracted three times with DCM. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure until no liquid flowed out, yielding 8.5 g of a pale yellow solid (compound III), with a yield of 86% and a purity of 98%.

[0078] Compound III: 1 H NMR(400MHz, CDCl3-d)δ6.73-6.69(m,1H),4.62-4.59(m,1H),4.39-4.36(m,2H),4.09(q,2H),3.45-3.43(m,1H),3.01-2.98 (m,1H),2.55-2.53(m,1H),2.35(s,3H),1.60-1.54(m,4H),1.45(s,9H),1.41(s,9H),1.23(t,3H),0.90(t,3H),0.83(t,3H); 13CNMR (101 MHz, CDCI3-d) δ 170.10, 166.53, 165.69, 136.07, 129.21, 83.41, 79.27, 78.69, 65.17, 61.20, 59.43, 46.97, 29.37, 28.91, 26.42, 26.22, 23.01, 21.03, 14.17, 9.69, 9.52; MS m / z 549.2 ([M+H] + )

[0079] Preparation of compound II of Example 5

[0080]

[0081] Into a 250ml three-necked flask, 10g of compound III and 80ml of trifluoroacetic acid were sequentially added, and the reaction was carried out under nitrogen protection and magnetic stirring at 65±5°C until the raw material was consumed. After cooling to room temperature, 100ml of H2O was added, and 2mol / L NaOH solution was added dropwise at room temperature to adjust the pH to 7-8. Then 100ml of dichloromethane was added, stirred for 10min, and then separated. The aqueous phase was extracted twice with DCM (50ml*2), and the organic phase was combined and concentrated under vacuum to obtain a crude product which was purified with ethyl acetate and n-heptane to obtain 5.9g of compound II with a yield of 84% and a purity of 98%.

[0082] Preparation of compound I of Example 6

[0083]

[0084] Into a 100ml three-necked flask, 9.4g of 85% phosphoric acid and 50ml of anhydrous ethanol were sequentially added, and the reaction was carried out under stirring at 65°C until the raw material was consumed. After cooling to 0±5°C, the reaction was continued for 2h under stirring at 0±5°C. Then the product was filtered, and the filter cake was washed with acetone and n-heptane and dried to obtain white crystalline solid I (15.4g, yield 78%, purity 99%).

[0085] Preparation of compound V of Comparative Example 1

[0086]

[0087] Into a 250ml three-necked flask, 6g of chlorosulfonyl isocyanate and 18ml of dioxane were sequentially added, and the reaction was carried out under stirring at room temperature. Then, 33g of t-butyl alcohol was added dropwise to the reaction system in dioxane (33g of t-butyl alcohol was dissolved in 33ml of dioxane), and the dropping temperature was controlled to be ≤10°C. After the dropping was completed, the reaction was continued at 0-10°C for 1h to obtain a dioxane solution of compound VIII.

[0088] In a 500ml three-necked flask, 10g of VII, 100ml of dioxane, stirring solution, then add 8.7g of triethylamine, temperature control 5±5℃ stirring 30min, prepared compound VIII dioxane solution slowly drop into the reaction system, drop in the process, control the drop temperature ≤10℃, after the drop is completed, the temperature is increased to 25℃, and the reaction is carried out. When the raw material is consumed, ice water is added to quench the reaction, dichloromethane is used for extraction 3 times (50ml*3), the organic phase is washed with 50ml of saturated sodium chloride, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 14.5g of crude product (i.e. compound VI). Dissolve in 150ml of dioxane, add 33.4g of triethylamine, protect with N2, and heat to 80℃ for reaction. When the raw material is consumed, cool to room temperature, add 50ml of water and 50ml of dichloromethane to the reaction system, extract and separate, wash the aqueous phase with dichloromethane twice, combine the organic phase, dry with anhydrous sodium sulfate, and then concentrate under reduced pressure to obtain the crude product (i.e. compound V). Recrystallize with ethyl acetate / n-heptane to obtain 3.9g of white solid, with a two-step yield of 32%, a purity of 98%, and nuclear magnetic resonance and mass spectrum consistent with example 1.

[0089] The above only describes the preferred embodiments of the present application and is not intended to limit the present application. For those skilled in the art, the present application can have various modifications and changes. Any modification, equivalent replacement, improvement, etc. within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for synthesizing oseltamivir, characterized in that, Includes the following steps: In step (1), compound VII reacts with compound VIII in a solvent and under the action of base 1 to obtain intermediate VI. Then, intermediate VI reacts with base 2 at a certain reaction temperature to obtain intermediate V. In step (2), intermediate V reacts with tert-butylamine in a solvent under Lewis acid catalysis to obtain intermediate IV; In step (3), intermediate IV reacts with an acetylation reagent in a solvent under the action of a base to obtain intermediate III; Step (4) involves reacting the intermediate of formula III under acidic conditions to prepare oseltamivir (formula II); in, The base 1 mentioned in step (1) is selected from one or more of triethylamine, tripropylamine, tributylamine, N,N-diisopropylethylamine, triethylenediamine, 1,8-diazabicycloundec-7-ene, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, and sodium ethoxide. The alkali 2 mentioned in step (1) is selected from sodium hydride; The Lewis acid mentioned in step (2) is selected from one or more of aluminum trichloride, ferric trichloride, zinc chloride, magnesium chloride, magnesium bromide, manganese chloride, nickel chloride, boron trifluoride ether, p-toluenesulfonic acid, or trifluoromethanesulfonic acid; The base mentioned in step (3) is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, triethylamine, N,N-diisopropylethylamine, triethylenediamine, 1,8-diazabicycloundec-7-ene, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, or sodium ethoxide. The acid mentioned in step (4) is selected from one or more of the following: hydrogen chloride ethanol solution, hydrogen chloride methanol solution, hydrogen chloride dioxane solution, hydrogen chloride ethyl acetate solution, or trifluoroacetic acid.

2. The synthesis method according to claim 1, characterized in that, The solvent mentioned in step (1) is selected from one or more of toluene, xylene, mesitylene, dioxane, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide, and N,N-dimethylformamide; And / or, the base 1 is selected from triethylamine; And / or, the certain reaction temperature mentioned in step (1) refers to 60-100℃; And / or, in step (1), the molar ratio of base 1 and compound of formula VII is (3-5):

1.

3. The synthesis method according to claim 2, characterized in that, The solvent mentioned in step (1) is dioxane; And / or, the certain reaction temperature mentioned in step (1) is 80°C; And / or, in step (1), the molar ratio of base 1 and compound of formula VII is 3:

1.

4. The synthesis method according to claim 1, characterized in that, The Lewis acid mentioned in step (2) is selected from magnesium chloride or magnesium bromide; And / or, the solvent in step (2) is selected from one or more of toluene, xylene, mesitylene, dioxane, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide or N,N-dimethylformamide.

5. The synthesis method according to claim 4, characterized in that, The solvent mentioned in step (2) is toluene.

6. The synthesis method according to claim 1, characterized in that, The acetylation reagent mentioned in step (3) is selected from acetyl chloride or acetic anhydride; And / or, the base described in step (3) is triethylamine; And / or, the solvent in step (3) is selected from one or more of toluene, xylene, mesitylene, dioxane, tetrahydrofuran, methyl tert-butyl ether, dichloromethane, 1,2-dichloroethane, acetonitrile, dimethyl sulfoxide or N,N-dimethylformamide.

7. The synthesis method according to claim 6, characterized in that, The acetylation reagent mentioned in step (3) is acetic anhydride; And / or, the solvent in step (3) is dichloromethane.

8. The synthesis method according to claim 1, characterized in that, The acid mentioned in step (4) is trifluoroacetic acid.

9. The synthesis method according to claim 1, characterized in that, The reaction described in step (4) is carried out at 50-100°C.

10. The synthesis method according to claim 9, characterized in that, The reaction described in step (4) is carried out at 60-70°C.

11. The synthesis method according to claim 1, characterized in that, Includes the following steps: Step (1) Dissolve compound VII in dioxane, add triethylamine, add dioxane solution of formula VIII dropwise, after the addition is complete, heat to 15-30℃ to react, after the reaction is complete, quench with ice water, extract with dichloromethane, take the organic layer and concentrate under reduced pressure to obtain intermediate of formula VI; Dissolve intermediate of formula VI in dioxane, add sodium hydride, heat to 60-100℃ to react, after the reaction is complete, extract with dichloromethane, take the organic layer and concentrate under reduced pressure to obtain intermediate of formula V; Step (2) First, Lewis acid, toluene and tert-butylamine are mixed to obtain Lewis acid-tert-butylamine complex. Then, intermediate V is dissolved in toluene, Lewis acid-tert-butylamine complex is added, and the temperature is raised to 55-65℃ for reaction. After the reaction is completed, it is extracted with dichloromethane, and the organic phase is concentrated under reduced pressure to obtain intermediate IV. Step (3) Mix the intermediate of formula IV, triethylamine, dichloromethane and acetic anhydride, react under N2 protection, and after the reaction is completed at 15-30℃, extract with dichloromethane, and concentrate the organic phase under reduced pressure to obtain the intermediate of formula III. Step (4) Mix the intermediate of Formula III with trifluoroacetic acid, heat to 60-70°C and react. After the reaction is complete, add water, add alkali to adjust the pH to 7-8, extract with dichloromethane, and concentrate the organic phase under reduced pressure to obtain oseltamivir (Formula II).

12. The synthesis method according to claim 11, characterized in that, Includes the following steps: Step (1) Dissolve compound VII in dioxane, add triethylamine, add dioxane solution of formula VIII dropwise, after the addition is complete, heat to 25°C to react, after the reaction is complete, quench with ice water, extract with dichloromethane, take the organic layer and concentrate under reduced pressure to obtain intermediate VI; Dissolve intermediate VI in dioxane, add sodium hydride, heat to 80°C under N2 protection to react, after the reaction is complete, extract with dichloromethane, take the organic layer and concentrate under reduced pressure to obtain crude intermediate V, and then recrystallize from ethyl acetate / n-heptane to obtain refined intermediate V; Step (2) First, Lewis acid, toluene, and tert-butylamine are mixed and reacted at 15-25℃ for 6 hours to obtain Lewis acid-tert-butylamine complex. Then, intermediate V is dissolved in toluene, Lewis acid-tert-butylamine complex is added, and the temperature is raised to 55-65℃ for reaction. After the reaction is completed, it is extracted with dichloromethane, and the organic phase is concentrated under reduced pressure to obtain crude intermediate IV. Then, it is recrystallized from ethyl acetate / n-heptane to obtain refined intermediate IV. The Lewis acid is selected from magnesium chloride or magnesium bromide. Step (3) Mix the intermediate of formula IV, triethylamine, dichloromethane and acetic anhydride, react under N2 protection, and after the reaction is completed at 15-30℃, quench with water, extract with dichloromethane, and concentrate the organic phase under reduced pressure to obtain the intermediate of formula III. Step (4) Mix the intermediate of Formula III with trifluoroacetic acid, heat to 60-70℃ and react. After the reaction is complete, add water, add sodium hydroxide to adjust the pH to 7-8, extract with dichloromethane, take the organic phase and concentrate under reduced pressure to obtain crude oseltamivir, and further pass through ethyl acetate and n-heptane to obtain refined oseltamivir.

13. The synthesis method according to claim 1, characterized in that, It also includes the following steps: Step (5) involves reacting oseltamivir obtained according to any one of claims 1 to 8 with phosphoric acid in a solvent via a salt formation reaction to obtain oseltamivir phosphate (Formula I): The solvent is selected from methanol, anhydrous ethanol, or propanol; And / or, the phosphoric acid is selected from 85% phosphoric acid; And / or, the temperature of the salt formation reaction is 60-70°C; And / or, step (5) further includes cooling and crystallization after salt formation with phosphate, wherein the cooling temperature is -5 to 5°C and the cooling and crystallization time is 2 hours.

14. The synthesis method according to claim 13, characterized in that, The solvent is anhydrous ethanol.

15. An oseltamivir intermediate compound, characterized in that, The compound is selected from:

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