阅读说明：本技术 一种奥司他韦的新合成方法 (Novel synthesis method of oseltamivir ) 是由 佟庆喆 王瑶 于 2021-02-01 设计创作，主要内容包括：本发明提供了一种奥司他韦的新合成方法,该方法以化合物(E)-2-(2-硝基乙烯基)异吲哚啉-1,3-二酮与丙酮酸乙酯为起始原料,在硫脲催化剂催化的条件下,发生Michael加成反应,得到相应的Michael加成产物；之后Michael加成产物与(甲酰基亚甲基)三苯基膦发生一锅内的Wittig反应与Henry反应得到关环产物；之后关环产物与三氯乙腈中间体形成醚化产物,经还原、乙酰化、脱保护,得到奥司他韦。本发明的反应路线六步且每步反应所用的原料都是易得的且不昂贵,操作简单,并且每步反应收率较高,在整个合成过程之中并没有重金属和叠氮化合物的使用,是绿色和安全的,可应用于工业生产。(The invention provides a new synthesis method of oseltamivir, which takes a compound (E) -2- (2-nitrovinyl) isoindoline-1, 3-diketone and ethyl pyruvate as starting raw materials to carry out Michael addition reaction under the condition of catalysis of a thiourea catalyst to obtain a corresponding Michael addition product; then the Michael addition product and (formyl methylene) triphenylphosphine are subjected to a Wittig reaction in a pot and are reacted with Henry to obtain a ring closing product; and then forming an etherification product by the ring closure product and a trichloroacetonitrile intermediate, and carrying out reduction, acetylation and deprotection to obtain oseltamivir. The method has six steps of reaction route, raw materials used in each step of reaction are easily available and inexpensive, the operation is simple, the reaction yield in each step is high, no heavy metal or azide is used in the whole synthesis process, and the method is green and safe and can be applied to industrial production.)

1. A new synthesis method of oseltamivir comprises the following steps:

(1) in a solvent A, under the action of a hydrogen bond catalyst and an acid catalyst 1, a compound shown in a formula I and a compound shown in a formula II are subjected to a Michael addition reaction to prepare a compound shown in a formula IV;

(2) preparing a compound of formula V by reacting a compound of formula IV with (formylmethylene) triphenylphosphine in a solvent B through a one-pot Wittig reaction with Henry;

(3) in a solvent C, under the action of an acid catalyst 2, a compound of a formula V and a compound of a formula VI are subjected to nucleophilic substitution reaction to construct an ether bond, and a compound of a formula VII is prepared;

(4) in a solvent D, carrying out nitro reduction reaction on a compound shown in a formula VII and stannous chloride dihydrate to obtain a reduction product; in a solvent E, under the action of triethylamine, carrying out acylation reaction on a reduction product and an acylation reagent to obtain a compound of a formula VIII;

(5) and carrying out deprotection reaction on the compound shown in the formula VIII to obtain oseltamivir.

2. The novel synthesis method of oseltamivir according to claim 1, wherein step (1) comprises one or more of the following conditions:

a. the solvent A is anhydrous dichloromethane or anhydrous toluene; the ratio of the volume of the solvent A to the mole number of the compound in the formula I is 6-15mL:1 mmol;

b. the hydrogen bond catalyst is one of a compound shown in a formula III-1, a compound shown in a formula III-2, a compound shown in a formula III-3, a compound shown in a formula III-4 and a compound shown in a formula III-5; the molar ratio of the hydrogen bond catalyst to the compound of the formula I is 0.01-0.2: 1;

c. the acidic catalyst 1 is acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, propionic acid, phenylacetic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, p-aminobenzoic acid or p-chlorobenzoic acid, preferably acetic acid; the molar ratio of the acidic catalyst 1 to the compound of formula I is 0.1-0.6:1, preferably 0.2-0.4: 1;

d. the molar ratio of the compound of the formula I to the compound of the formula II is 1:1-2.0, preferably 1: 1.5.

3. The novel synthesis method of oseltamivir according to claim 1, wherein step (1) comprises one or more of the following conditions:

a. the Michael addition reaction temperature is 25-35 ℃, and 25 ℃ is preferred; the Michael addition reaction time is 12-24h, preferably 15-20 h;

b. the preparation method of the compound shown in the formula IV by the Michael addition reaction of the compound shown in the formula I and the compound shown in the formula II comprises the following steps: dissolving a compound of formula I in 75-85% of a solvent A; dissolving a compound shown in the formula II in the rest solvent A to obtain a compound solution shown in the formula II, adding the compound solution shown in the formula II into a system containing the compound shown in the formula I, adding a hydrogen bond catalyst and an acid catalyst 1, and reacting at the temperature of 25-35 ℃; the reaction is carried out under argon atmosphere;

c. the method for post-treating the reaction liquid obtained by the reaction of the compound of the formula I and the compound of the formula II comprises the following steps: distilling the obtained reaction liquid under reduced pressure to remove the solvent, and purifying the obtained product by utilizing silica gel column chromatography to obtain a compound shown in the formula IV; the silica gel is 200-mesh 300-mesh silica gel; and the eluent for column chromatography is petroleum ether: ethyl acetate: dichloromethane-4: 1:1 mixed solvent, or petroleum ether: ethyl acetate 3: 1.

4. The novel synthesis method of oseltamivir according to claim 1, characterized in that step (2) comprises one or more of the following conditions:

a. the solvent B is anhydrous tetrahydrofuran, anhydrous dichloromethane or anhydrous toluene; the ratio of the volume of the solvent B to the mole number of the compound shown in the formula IV is 10-30mL:1 mmol;

b. the molar ratio of the compound shown in the formula IV to the (formylmethylene) triphenylphosphine is 1: 1-1.5; the (formyl methylene) triphenylphosphine is added into a reaction system in two batches, and the addition time interval is 4-6 minutes;

c. the temperature of the Wittig reaction and the Henry reaction is 20-60 ℃, and the reaction time is 4-15 h; the reaction was carried out under an argon atmosphere.

5. The novel synthesis method of oseltamivir according to claim 1, wherein the post-treatment method of the reaction solution obtained by the reaction of the compound of formula IV in step (2) and (formylmethylene) triphenylphosphine is as follows: distilling the reaction solution under reduced pressure to remove the solvent, separating and purifying by first silica gel column chromatography to obtain a compound of the formula V and an epimer V-1 mixture thereof, and then separating the mixture by second silica gel column chromatography to obtain a compound of the formula V;

the silica gel for the first silica gel column chromatography is 200-300-mesh silica gel, and the eluent is petroleum ether in volume ratio: ethyl acetate 4: 1;

the silica gel for the second silica gel column chromatography is 200-300-mesh silica gel, and the eluent is chloroform: ethyl acetate 10:1 mixed solvent.

6. The novel synthesis method of oseltamivir according to claim 1, characterized in that step (3) comprises one or more of the following conditions:

a. the solvent C is anhydrous dichloromethane; the ratio of the volume of the solvent C to the mole number of the compound of the formula V is 40-60mL:1 mmol;

b. the acid catalyst 2 is trifluoromethanesulfonic acid; the molar ratio of the acidic catalyst 2 to the compound of the formula V is 5-20:1, preferably 8-15: 1;

c. the molar ratio of the compound of the formula V to the compound of the formula VI is 1:40-60, preferably 1: 45-55.

7. The novel synthesis method of oseltamivir according to claim 1, wherein the step of preparing the compound of formula vii in step (3) is: adding a compound shown in the formula V into a solvent C, then adding a compound shown in the formula VI, heating to 50 ℃, refluxing, and adding an acidic catalyst 2 for reaction; the reaction is carried out under argon atmosphere;

the temperature of the nucleophilic substitution reaction is 50 ℃, and the time of the nucleophilic substitution reaction is 8-10 h;

the post-treatment method of the reaction liquid obtained in the preparation of the compound shown in the formula VII is as follows: cooling the reaction system to 0 ℃, adding a saturated sodium bicarbonate solution under the stirring condition to quench the reaction, filtering to remove solid impurities, extracting the filtrate with dichloromethane, drying the obtained dichloromethane phase with anhydrous sodium sulfate, removing the solvent, and purifying the obtained product by silica gel column chromatography to obtain a compound shown in the formula VII; the silica gel for silica gel column chromatography is 200-300-mesh silica gel, and the eluent is petroleum ether in volume ratio: ethyl acetate 10:1 mixed solvent.

8. The novel synthesis method of oseltamivir according to claim 1, characterized in that step (4) comprises one or more of the following conditions:

a. the solvent D is a mixed solvent of tetrahydrofuran and distilled water, and the volume ratio of the tetrahydrofuran to the distilled water in the mixed solvent is 6-10:1, preferably 8: 1;

b. the ratio of the volume of the solvent D to the mole number of the compound of the formula VII is 10-30mL:1 mmol;

c. the molar ratio of the compound shown in the formula VII to the stannous chloride dihydrate is 5-15:1, preferably 8-12: 1;

d. the temperature of the nitro reduction reaction is 40-60 ℃, and preferably 50 ℃; the nitro reduction reaction time is 18-36h, preferably 20-24 h; the reaction is carried out under argon atmosphere;

e. the post-treatment method of the reaction liquid obtained by the nitro reduction reaction comprises the following steps: the reaction solution was cooled to room temperature, the reaction was quenched with a saturated sodium bicarbonate solution, filtered, the resulting filtrate was separated, the aqueous phase was extracted with ethyl acetate, and then the resulting ethyl acetate phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain a reduced product.

9. The novel synthesis method of oseltamivir according to claim 1, characterized in that step (4) comprises one or more of the following conditions:

a. the solvent E is anhydrous dichloromethane; the acylating reagent is acetyl chloride, and the acylating reagent is added into the system in a dropwise manner; the ratio of the number of moles of the acylating agent to the volume of solvent E is 1mmol:3-6 mL; the molar ratio of the acylating reagent to the compound of the formula VII is 2-3: 1;

b. the molar ratio of the triethylamine to the acylating reagent is 1-1.5: 1;

c. the acylation reaction temperature is room temperature; the reaction time is 6-10 h;

d. the acylation reaction comprises the following steps: adding the obtained reduction product into a solvent E under the argon atmosphere, adding triethylamine, then cooling to-10 ℃, dropwise adding an acylating agent, and after dropwise adding is completed, heating to room temperature for acylation reaction to obtain a compound of the formula VIII;

e. the post-treatment method of the reaction liquid obtained by the acylation reaction comprises the following steps: after the reaction is finished, adding a saturated sodium bicarbonate solution into the reaction solution to quench the reaction, filtering, separating the filtrate, extracting the water phase with dichloromethane, drying the obtained dichloromethane phase with anhydrous sodium sulfate, removing the solvent, and purifying the obtained product by silica gel column chromatography to obtain a white oily substance, namely the compound of the formula VIII; the silica gel for silica gel column chromatography is 200-300-mesh silica gel, and the eluent is n-hexane in volume ratio: ethyl acetate 3: 1.

10. The novel synthesis method of oseltamivir according to claim 1, wherein the deprotection reaction in step (5) comprises the steps of:

dissolving the compound of formula VIII in absolute ethyl alcohol, adding an ethanol solution of hydrazine, reacting at 60-70 ℃ for 10-15 hours, and carrying out post-treatment to obtain oseltamivir;

the ratio of the volume of the absolute ethyl alcohol to the mole number of the compound of the formula VIII is 10-30mL:1 mmol;

the concentration of hydrazine in the hydrazine ethanol solution is 0.5-1.5mol/L, and the molar ratio of hydrazine in the hydrazine ethanol solution to the compound of the formula VIII is 4-6: 1;

the post-treatment method of the reaction liquid obtained by the deprotection reaction comprises the following steps: after the reaction is finished, adding ether into the reaction liquid to separate out a precipitate, then filtering, removing the solvent from the obtained filtrate, and then purifying the obtained product by silica gel column chromatography to obtain a yellow oily substance, namely oseltamivir; the silica gel used for silica gel column chromatography is 200-300 mesh silica gel, and the eluent is dichloromethane in volume ratio: methanol is a 5:1 mixed solvent.

Technical Field

The invention relates to a novel synthesis method of oseltamivir, belonging to the technical field of drug synthesis.

Background

Oseltamivir is a neuraminidase inhibitor, synthesized for the first time in 1996, marketed in switzerland in 1999 after being developed by roche corporation, and launched in the market in china in 2002, has certain pharmaceutical activity in resisting atypical pneumonia in 2003, and quickly becomes an important reserve medicine for preventing and controlling influenza in the world health organization and China. The molecular formula of oseltamivir is C₁₆H₂₈N₂O₄The chemical name is: the structural formula of the (3R,4R,5S) -4-acetamide-5-amino-3- (1-propoxyethyl) -1-cyclohexene-1-carboxylic acid ethyl ester is shown as the following formula. To date, oseltamivir (or oseltamivir phosphate, also known as tetramefovir or tamiflu) is the world-recognized most effective drug against avian influenzaEffective drugs, and therefore, its synthesis and industrialization are very important.

At present, in the prior art, the preparation methods of oseltamivir mainly include the following methods:

the synthetic route jointly developed by Gilead corporation and Roche corporation of Switzerland in the United states utilizes shikimic acid as a raw material, and the synthetic route is as follows: starting from shikimic acid, performing thionyl chloride acetylation, performing esterification reaction with ethanol, performing ketal protection, hydroxyl protection, ketal exchange, selective reduction, intramolecular ring oxidation, ring opening of epoxy intermediate azide, amino acetylation and azide reduction to obtain oseltamivir. The amino group of the drug containing the amino group is easily oxidized, and the amino group is often protonated with an acid to form hydrochloride or sulfate phosphate, etc. to increase the stability, so oseltamivir is often prepared in the form of its phosphate, which is under the trade name tamiflu, and the reaction process is described as the following synthetic scheme 1.

The synthetic route 1 has the advantages that the operation is relatively simple, the industrialization is realized, the defect is that the route needs 11 steps of reaction for oseltamivir, the total yield is only 20%, the reaction steps are long, the raw material shikimic acid is extracted from a natural product (a traditional Chinese medicine which is abundant in southeast Asia-star aniseed), the synthetic capacity of the oseltamivir is limited due to the limited capacity of the star aniseed, the large-scale requirement cannot be met, although the process is continuously improved by Roche company, the reaction yield cannot be obviously improved, and in addition, the explosive raw material NaN₃The use of (A) also has certain potential safety hazard. Therefore, the development of a simple and safe method for synthesizing oseltamivir from chemical raw materials is a problem to be solved urgently.

In 2006, E.J. Corey et al (J.Am.chem.Soc.2006,128,6310-6311) reported asymmetric Diels-Alder reactions catalyzed by chiral oxazaborolidine to synthesize oseltamivir completely, and they synthesized oseltamivir using 1, 3-butadiene as a raw material. The oseltamivir is obtained by asymmetric Diels-Alder reaction, ester ammonolysis, iodine-catalyzed intramolecular amidation, amino protection, elimination under base catalysis, free radical reaction, conjugate elimination under base catalysis, double bond addition, intramolecular cyclic amidation and ring opening of tricyclic amide under Lewis acid catalysis, and the reaction process is described as the following synthetic route 2. However, this route has a long reaction step, is not particularly high in relative yield, and uses a complicated chiral oxazaborolidine catalyst, thus having great limitations in industrial applications.

Professor Hayashi in 2009 in japan reports a synthetic route of oseltamivir catalyzed by a chiral proline derivative in a one-pot method, and the synthesis route realizes four-step chemical reaction of the one-pot method, and realizes higher synthetic yield of oseltamivir, which reaches 57%. But the method adopts an expensive and not easily available organic small molecule proline catalyst, so that the method is only limited to laboratory synthesis at present and is difficult to realize industrialization, and in the synthetic route, an explosive reagent sodium azide still needs to be used, and the factors limit the application of the method in industrial production, and the reaction process is described as the following synthetic route 3.

The full synthesis of oseltamivir was achieved in 2010 by the major professor team of horses (angelw. chem. int. ed.2010,49, 4656-containing 4660) using a chiral proline catalyst substituted with dinaphthyl, requiring only five reactions, the reaction procedure being depicted as scheme 4 below. The method avoids the use of explosive reagent sodium azide, the synthesis route is the shortest at present, but the synthesis method with simple and easily obtained raw materials and catalysts still needs to be further developed.

Hao project group (J.Am. chem. Soc.2018,140,10619-10626) in 2018 achieved full synthesis of oseltamivir with iron catalyzed alkene double azide reaction as the key step, but this route step was long and required the use of azide compounds and the overall yield was not ideal, the reaction key step is depicted as synthetic route 5 below.

Currently, the economy and safety of the existing oseltamivir synthetic route are to be further improved. Therefore, the development of a synthetic method of oseltamivir, which has the advantages of simple and safe raw materials, short synthetic route, safe and simple operation and low cost, is an urgent problem to be solved. The invention is therefore proposed.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a novel synthesis method of oseltamivir. The raw materials used in the method are simple and safe, and the cost is low; short preparation steps, simple operation and strong practicability.

Description of terms:

a compound of formula I: (E) -2- (2-nitrovinyl) isoindoline;

a compound of formula II: ethyl pyruvate;

a compound of formula III-1: 1- ((1R,2R) -2-aminocyclohexyl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea;

a compound of formula III-2: (R) -1- (2 '-amino- [1,1' -binaphthyl ] -2-yl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea;

a compound of formula III-3: n- [ (1R, 2R-2-amino-1, 2-diphenylethyl ] benzenesulfinamide;

a compound of formula III-4: 1- ((1R,2R) -2-amino-1, 2-diphenylethyl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea;

a compound of formula III-5: 3- ((1R,2R) -amino-1, 2-diphenyldiethyl) -4- ((3, 5-bis (trifluoromethyl) phenyl) amino) cyclobut-3-ene-1, 2-dione;

a compound of formula IV: 4- (1, 3-dioxoisoindol-2-yl) -5-nitro-2-oxopentanoic acid ethyl ester;

a compound of formula V: (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylic acid ethyl ester;

a compound of formula V-1: (3S,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylic acid ethyl ester;

a compound of formula VI: the chemical name of the trichloroacetonitrile intermediate is as follows: 3-pentyltrichloroacetimidate;

a compound of formula VII: (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -4-nitro-3- (pentyl-3-yloxy) cyclohex-1-ene-1-carboxylic acid ethyl ester;

a compound of formula VIII: (3R,4R,5S) -4-acetylamino-5- (1, 3-dioxoisoindol-2-yl) -3- (pentyl-3-yloxy) cyclohex-1-ene-1-carboxylic acid ethyl ester.

The compound numbers in the specification are completely consistent with the structural formula numbers, have the same reference relationship, and are based on the structural formula of the compound.

Room temperature: having a meaning well known in the art, meaning 25. + -. 5 ℃.

The technical scheme of the invention is as follows:

a new synthesis method of oseltamivir comprises the following steps:

(1) in a solvent A, under the action of a hydrogen bond catalyst and an acid catalyst 1, a compound shown in a formula I and a compound shown in a formula II are subjected to a Michael addition reaction to prepare a compound shown in a formula IV;

(2) preparing a compound of formula V by reacting a compound of formula IV with (formylmethylene) triphenylphosphine in a solvent B through a one-pot Wittig reaction with Henry;

(3) in a solvent C, under the action of an acid catalyst 2, a compound of a formula V and a compound of a formula VI are subjected to nucleophilic substitution reaction to construct an ether bond, and a compound of a formula VII is prepared;

(4) in a solvent D, carrying out nitro reduction reaction on a compound shown in a formula VII and stannous chloride dihydrate to obtain a reduction product; in a solvent E, under the action of triethylamine, carrying out acylation reaction on a reduction product and an acylation reagent to obtain a compound of a formula VIII;

(5) and carrying out deprotection reaction on the compound shown in the formula VIII to obtain oseltamivir.

According to the invention, the solvent A in the step (1) is anhydrous dichloromethane or anhydrous toluene; the ratio of the volume of the solvent A to the mole number of the compound of the formula I is 6-15mL:1 mmol.

According to the invention, the hydrogen bond catalyst in the step (1) is preferably one of a compound shown in a formula III-1, a compound shown in a formula III-2, a compound shown in a formula III-3, a compound shown in a formula III-4 and a compound shown in a formula III-5:

according to the present invention, the hydrogen bonding catalyst is commercially available, or is referred to in Liu, y.; kang, t.r.; liu, q.z.; chen, l.m.; wang, y.c.; liu, j.; xie, y.m.; yang, j.l.; he, L.org.Lett.2013,15, 6090-; or Galzenano, Patrizia; benivenni, Giorgio; pesciaioli, Fabio; mazzarnti, Andrea; giannichi, Berardino; sambri, Letizia; bartoli, Giuseppe; melchiorre, Paolo, chem.Eur.J., 2009,15, 7846-; or didarskou, Christos; kupai, Jozsef; cseri, Levente; barabas, Julia; vass, Elemer; holtzl, Tibor; szekely, Gyorgy, ACS Catalysis,2018,8, 7430-one 7438.

According to the invention, the molar ratio of the hydrogen bond catalyst to the compound of formula I in step (1) is preferably from 0.01 to 0.2: 1.

According to the present invention, the acidic catalyst 1 in the step (1) is preferably acetic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, propionic acid, phenylacetic acid, p-nitrobenzoic acid, p-methoxybenzoic acid, p-aminobenzoic acid or p-chlorobenzoic acid, and further preferably acetic acid; the molar ratio of the acidic catalyst 1 to the compound of formula I is 0.1-0.6:1, more preferably 0.2-0.4: 1.

According to the invention, the molar ratio of the compound of formula I to the compound of formula II in step (1) is preferably 1:1 to 2, more preferably 1: 1.5; the preparation of said compounds of formula i is described in the literature: D.W.Ma et al, Angew.chem.Int.Ed.2010,49, 4656-containing 4660.

According to the present invention, the temperature of the Michael addition reaction in step (1) is preferably 25 to 35 ℃, and more preferably 25 ℃; the Michael addition reaction time is 12-24h, and more preferably 15-20 h.

According to a preferred embodiment of the present invention, the step of preparing the compound of formula IV by Michael addition reaction of the compound of formula I and the compound of formula II in step (1) comprises: dissolving a compound of formula I in 75-85% of a solvent A; dissolving the compound of the formula II in the rest solvent A to obtain a compound solution of the formula II, adding the obtained compound solution of the formula II into a system containing the compound of the formula I, then adding a hydrogen bond catalyst and an acid catalyst 1, and carrying out reaction at 25-35 ℃.

Preferably, according to the invention, the reaction in step (1) is carried out under an argon atmosphere.

According to a preferred embodiment of the present invention, the reaction mixture obtained in step (1) by reacting the compound of formula I with the compound of formula II is worked up as follows: distilling the obtained reaction liquid under reduced pressure to remove the solvent, and purifying the obtained product by utilizing silica gel column chromatography to obtain a compound shown in the formula IV; the silica gel is 200-mesh 300-mesh silica gel; and the eluent for column chromatography is petroleum ether: ethyl acetate-dichloromethane-4: 1:1 mixed solvent, or petroleum ether: ethyl acetate 3: 1.

According to the invention, the solvent B in the step (2) is preferably anhydrous tetrahydrofuran, anhydrous dichloromethane or anhydrous toluene; the ratio of the volume of the solvent B to the mole number of the compound shown in the formula IV is 10-30mL:1 mmol.

According to the invention, the molar ratio of the compound of formula IV to (formylmethylene) triphenylphosphine in step (2) is preferably 1:1 to 1.5; the (formyl methylene) triphenylphosphine is added into a reaction system in two batches, and the addition time interval is 4-6 minutes; the (formylmethylene) triphenylphosphine was added in portions to allow complete dissolution and to avoid the ylide itself reacting.

Preferably, the temperature of the Wittig reaction and the Henry reaction in the step (2) is 20-60 ℃, and the reaction time is 4-15 h; the reaction was carried out under an argon atmosphere.

According to the invention, the compound of formula IV in the step (2) is subjected to a Wittig reaction and a Henry reaction by a one-pot method to obtain a compound of formula V and an epimer thereof, wherein the structural formula of the epimer is shown as a formula V-1:

according to the invention, the reaction solution obtained by reacting the compound of formula IV in step (2) with (formylmethylene) triphenylphosphine is preferably worked up as follows: distilling the reaction solution under reduced pressure to remove the solvent, separating and purifying by first silica gel column chromatography to obtain a compound of the formula V and an epimer V-1 mixture thereof, and then separating the mixture by second silica gel column chromatography to obtain a compound of the formula V;

further preferably, the silica gel for the first silica gel column chromatography is 200-300 mesh silica gel, and the eluent is petroleum ether: ethyl acetate 4: 1;

further preferably, the silica gel for the second silica gel column chromatography is 200-300 mesh silica gel, and the eluent is chloroform: ethyl acetate 10:1 mixed solvent.

According to the invention, the solvent C in the step (3) is preferably anhydrous dichloromethane; the ratio of the volume of the solvent C to the number of moles of the compound of formula V is 40-60mL:1 mmol.

Preferably according to the present invention, the acidic catalyst 2 in step (3) is trifluoromethanesulfonic acid; the molar ratio of the acidic catalyst 2 to the compound of formula V is 5-20:1, and more preferably 8-15: 1.

According to a preferred embodiment of the invention, the molar ratio of the compound of the formula V to the compound of the formula VI in step (3) is from 1:40 to 60, more preferably from 1:45 to 55.

Preferably, according to the invention, the step of preparing the compound of formula VII in step (3) is: adding a compound shown in the formula V into a solvent C, then adding a compound shown in the formula VI, heating to 50 ℃, refluxing, and adding an acidic catalyst 2 for reaction; the reaction was carried out under an argon atmosphere.

According to the invention, references are made to the preparation of said compounds of formula VI: J.am.chem.Soc.2018,140, 10619-10626.

According to the invention, the temperature of the nucleophilic substitution reaction in the step (3) is 50 ℃, and the time of the nucleophilic substitution reaction is 8-10 h.

According to a preferred embodiment of the present invention, the post-treatment of the reaction solution obtained in step (3) for preparing the compound of formula VII is: cooling the reaction system to 0 ℃, adding a saturated sodium bicarbonate solution under the stirring condition to quench the reaction, filtering to remove solid impurities, extracting the filtrate with dichloromethane, drying the obtained dichloromethane phase with anhydrous sodium sulfate, removing the solvent, and purifying the obtained product by silica gel column chromatography to obtain a compound shown in the formula VII; the silica gel for silica gel column chromatography is 200-300-mesh silica gel, and the eluent is petroleum ether in volume ratio: ethyl acetate 10:1 mixed solvent.

According to the present invention, the solvent D in step (4) is a mixed solvent of tetrahydrofuran and distilled water, and the volume ratio of tetrahydrofuran to distilled water in the mixed solvent is 6-10:1, and more preferably 8: 1; the ratio of the volume of the solvent D to the mole number of the compound of the formula VII is 10-30mL:1 mmol.

According to the invention, the molar ratio of the compound of the formula VII to stannous dichloride dihydrate described in step (4) is preferably from 5 to 15:1, more preferably from 8 to 12: 1.

According to the present invention, the nitro reduction reaction temperature in the step (4) is preferably 40 to 60 ℃, and more preferably 50 ℃; the nitro reduction reaction time is 18-36h, and the preferable time is 20-24 h; the reaction was carried out under an argon atmosphere.

According to the present invention, the post-treatment method of the reaction solution obtained by the nitro reduction reaction in the step (4) is preferably: the reaction solution was cooled to room temperature, the reaction was quenched with a saturated sodium bicarbonate solution, filtered, the resulting filtrate was separated, the aqueous phase was extracted with ethyl acetate, and then the resulting ethyl acetate phase was dried over anhydrous sodium sulfate, and the solvent was removed to obtain a reduced product.

According to the invention, the solvent E in the step (4) is preferably anhydrous dichloromethane; the acylating reagent is acetyl chloride, and the acylating reagent is added into the system in a dropwise manner; the ratio of the mole number of the acylation reagent to the volume of the solvent E is 1mmol:3-6 mL; the molar ratio of the acylating agent to the compound of the formula VII is 2-3: 1.

According to the invention, the molar ratio of the triethylamine to the acylating agent in the step (4) is preferably 1-1.5: 1.

According to the present invention, the acylation reaction temperature in the step (4) is preferably room temperature; the reaction time is 6-10 h.

Preferably according to the invention, the acylation in step (4) is carried out by: and under the argon atmosphere, adding the obtained reduction product into a solvent E, adding triethylamine, then cooling to-10 ℃, dropwise adding an acylating agent, and after dropwise adding is completed, heating to room temperature for acylation reaction to obtain the compound of the formula VIII.

According to the present invention, the post-treatment method of the reaction solution obtained by the acylation reaction in the step (4) is preferably: after the reaction is finished, adding a saturated sodium bicarbonate solution into the reaction solution to quench the reaction, filtering, separating the filtrate, extracting the water phase with dichloromethane, drying the obtained dichloromethane phase with anhydrous sodium sulfate, removing the solvent, and purifying the obtained product by silica gel column chromatography to obtain a white oily substance, namely the compound of the formula VIII; the silica gel for silica gel column chromatography is 200-300-mesh silica gel, and the eluent is n-hexane in volume ratio: ethyl acetate 3: 1.

According to the present invention, it is preferable that the deprotection reaction of said VIII compound in the step (5) is referred to: angew.chem.int.ed.2010,49, 4656-4660); preferably, the deprotection reaction comprises the steps of:

dissolving the compound of formula VIII in absolute ethyl alcohol, adding an ethanol solution of hydrazine, reacting at 60-70 ℃ for 10-15 hours, and carrying out post-treatment to obtain oseltamivir;

further preferably, the ratio of the volume of the absolute ethyl alcohol to the number of moles of the compound of formula VIII is 10-30mL:1 mmol.

Further preferably, the concentration of hydrazine in the hydrazine ethanol solution is 0.5-1.5mol/L, and the molar ratio of hydrazine in the hydrazine ethanol solution to the compound of the formula VIII is 4-6: 1;

further preferably, the post-treatment method of the reaction solution obtained by the deprotection reaction comprises: after the reaction is finished, adding ether into the reaction liquid to separate out a precipitate, then filtering, removing the solvent from the obtained filtrate, and then purifying the obtained product by silica gel column chromatography to obtain a yellow oily substance, namely oseltamivir; the silica gel used for silica gel column chromatography is 200-300 mesh silica gel, and the eluent is dichloromethane in volume ratio: methanol is a 5:1 mixed solvent.

The synthetic route of the method of the invention is as follows:

the invention has the following technical characteristics and beneficial effects:

1. the synthesis method of oseltamivir takes a compound (E) -2- (2-nitrovinyl) isoindoline-1, 3-diketone (phthaloyl is selected as a protective group of amino) and ethyl pyruvate as initial raw materials, and performs Michael addition reaction under the condition of catalysis of a thiourea catalyst to obtain a corresponding Michael addition product; then the Michael addition reaction product and 2- (triphenylphosphine) acetaldehyde are subjected to a Wittig reaction in a pot and reacted with Henry to obtain a ring closing product; then reacting the trichloroacetonitrile intermediate with hydroxyl in a closed-loop product to form ether, and successfully introducing 3-pentyl into the closed-loop product; and then, only some simple reduction is needed to be carried out, the nitro group is reduced into amino, acetylation is carried out, and finally deprotection is carried out, so that the oseltamivir product can be efficiently obtained. The key reaction in the invention is a Michael addition reaction of a compound (E) -2- (2-nitro) isoindoline-1, 3-diketone (phthaloyl is selected as a protective group of amino) and ethyl pyruvate under the catalysis of a thiourea catalyst, wherein the compound shown in a structural formula IV, the compound shown in a structural formula V, the compound shown in a structural formula VI and the compound shown in a structural formula VII are new compounds. Compared with the prior synthesis route, the synthesis route of the invention has only six steps, the raw materials used in each step of reaction are easily available and inexpensive, the operation is simple, each step of reaction has higher yield, and the heavy metal and the azide are not used in the whole synthesis process, thus the synthesis route is green and safe.

2. The invention starts from simple, cheap, convenient and easily obtained raw materials, and closes the ring through Michael addition reaction, Wittig reaction and Henry reaction, through ether bond construction, nitro reduction protection, acetylation reaction, removal of the phthaloyl protecting group, the oseltamivir is successfully synthesized in five steps, the steps of multi-step ring closing, ring opening and deprotection are saved, the total reaction steps are shortened, meanwhile, the preparation process has mild conditions and simple operation, so the oseltamivir synthetic route can be further amplified in a pilot plant test and applied to industrial production, and the preparation of the chiral catalyst used in the invention is not difficult, the raw materials of other intermediates can be synthesized only by the most basic industrial raw materials, thereby greatly improving the utilization efficiency of synthesis, and in addition, in the invention, heavy metal is not used, so that the oseltamivir synthesized by the method can effectively avoid heavy metal residue.

Detailed Description

The present invention is further illustrated by, but not limited to, the following examples.

The raw materials and reagents used in the examples are all commercially available products. In the examples, "%" is given by weight unless otherwise specified. The yields in the examples are all molar yields.

Hydrogen bond catalyst N- [ (1R, 2R-2-amino-1, 2-diphenylethyl ] benzene sulfinamide (III-3 catalyst) xylonite drug chiral technology (Shanghai) Co., Ltd. is available under CAS number 603996-85-6.

Preparation example 1

A preparation method of a hydrogen bond catalyst 1- ((1R,2R) -2-aminocyclohexyl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea (III-1) comprises the following steps:

(1R,2R) -1, 2-cyclohexanediamine (910.0mg,8.0mmol) was added to 40mL of anhydrous tetrahydrofuran, and then 3, 5-bis (trifluoromethyl) phenylisothiocyanate (1.46mL,8.0mmol) was added dropwise to the system at 0 ℃ with stirring for 45 minutes; after the dropwise addition, heating to room temperature, stirring at room temperature for reaction for 4 hours, distilling under reduced pressure to remove the solvent, purifying the obtained product by silica gel column chromatography, wherein an eluent is a mixed solvent of dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 100: 1-20: 1;

the product was obtained as a white flaky solid (2.81g, 91% yield), which was 1- ((1R,2R) -2-aminocyclohexyl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea (III-1). Reference documents: liu, y.; kang, t.r.; liu, q.z.; chen, l.m.; wang, y.c.; liu, j.; xie, y.m.; yang, j.l.; he, L.org.Lett.2013,15, 6090-.

The reaction equation is as follows:

preparation example 2

A process for the preparation of a hydrogen bonding catalyst (R) -1- (2 '-amino- [1,1' -binaphthyl ] -2-yl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea (iii-2) comprising the steps of:

(R) - (+) -1,1' -bi-2-naphthylamine (610.0mg, 2.16mmol) was added to 9 under an argon atmospheremL dry CH₂Cl₂Then, 3, 5-bis (trifluoromethyl) phenylisothiocyanate (329.0mg, 1.8mmol) was added dropwise to the above system at 0 ℃ with stirring for 45 minutes; after the dropwise addition, the temperature is raised to room temperature, and the reaction is stirred at room temperature for 4 hours; and (3) after the reaction is finished, removing the solvent by reduced pressure distillation, and purifying the obtained product by silica gel column chromatography, wherein the eluent is petroleum ether: ethyl acetate 10:1 to give (R) -1- (2 '-amino- [1,1' -binaphthyl) as a pale yellow solid product (590.0mg, yield 63%)]-2-yl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea (iii-2). Reference documents: galzeano, Patrizia; benivenni, Giorgio; pesciaioli, Fabio; mazzarnti, Andrea; giannichi, Berardino; sambri, Letizia; bartoli, Giuseppe; melchiorre, Paolo, chem. Eur. J,2009,15, 7846-.

The reaction equation is as follows:

preparation example 3

A preparation method of a hydrogen bond catalyst 1- ((1R,2R) -2-amino-1, 2-diphenylethyl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea (III-4) comprises the following steps:

(1R,2R) -1, 2-diphenylethylenediamine (910.0mg,8.0mmol) was added to 10mL of tetrahydrofuran, followed by dropwise addition of 3, 5-bis (trifluoromethyl) phenylisothiocyanate (1.46mL,8.0mmol) at 0 ℃ with stirring for 45 minutes; after the dropwise addition is finished, heating the reaction system to room temperature, and stirring and reacting for 4 hours at room temperature; and distilling the reaction liquid under reduced pressure to remove the solvent, and purifying the obtained product by silica gel column chromatography, wherein an eluent is a mixed solvent of dichloromethane and methanol, the volume ratio of the dichloromethane to the methanol is 30: 1-20: 1, and a white flaky solid (2.23g, yield 83%) is obtained, namely 1- ((1R,2R) -2-amino-1, 2-diphenyl ethyl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea (III-4). Reference documents: galzeano, Patrizia; benivenni, Giorgio; pesciaioli, Fabio; mazzarnti, Andrea; giannichi, Berardino; sambri, Letizia; bartoli, Giuseppe; melchiorre, Paolo, chem. Eur. J,2009,15, 7846-.

The reaction equation is as follows:

preparation example 4

A process for the preparation of a hydrogen bonding catalyst, 3- ((1R,2R) -amino-1, 2-diphenyldiethyl) -4- ((3, 5-bis (trifluoromethyl) phenyl) amino) cyclobut-3-ene-1, 2-dione (iii-5), comprising the steps of:

(1R,2R) -1, 2-Diphenylethylenediamine (223.0uL,1.0mmol) was added to the mono amide (3- ((3, 5-bis (trifluoromethyl) phenyl) amino) -4-methoxycyclobut-3-ene-1, 2-dione) (339.0mg, 1.0mmol), the reaction was stirred at room temperature and monitored by TLC until (1R,2R) -1, 2-diphenylethylenediamine was reacted completely; after the reaction is finished, the solvent is removed by reduced pressure distillation, and the obtained product is purified by column chromatography, wherein the eluent is dichloromethane in volume ratio: methanol 10:1 mixed solvent, to give the product as a white solid (226.0mg, 43% yield), i.e. 3- ((1R,2R) -amino-1, 2-diphenyldiethyl) -4- ((3, 5-bis (trifluoromethyl) phenyl) amino) cyclobut-3-ene-1, 2-dione (iii-5). Reference documents: didarskou, Christos; kupai, Jozsef; cseri, Levente; barabas, Julia; vass, Elemer; holtzl, Tibor; szekely, Gyorgy, ACS Catalysis,2018,8, 7430-.

The reaction equation is as follows:

preparation example 5

(E) A process for the preparation of (i) -2- (2-nitrovinyl) isoindoline (i), comprising the steps of:

(1) nitromethane (69.4mL, 1.25mol), triethyl orthoformate (83.3mL, 0.50mol), N-methylaniline (40.7mL, 0.375mol) and p-toluene sulfonic acid TsOH (2.0g, 0.01mol) were added to a 500mL round flask and reacted at 90 ℃ under reflux for 7 hours; after the reaction is finished, drying the reaction mixture under vacuum, washing the crude residue obtained after drying by using petroleum ether, purifying the product obtained after washing by using an alumina column, and eluting by using dichloromethane; the product from column chromatography was further purified by recrystallization from toluene/petroleum ether in an amount such that the product from column chromatography was just completely dissolved at a toluene to petroleum ether volume ratio of 1:2-5 to give a yellow crystalline product (41.3g, 62%).

The reaction equation of this step is as follows:

(2) the yellow crystalline product from step (1) (10.0g, 0.05mol) was dissolved in 40mL chloroform, 100mL of 7.0mol/L ammonia in MeOH was added, and the resulting mixture was stirred at-10 ℃ overnight for 11 h; after completion of the reaction, the solvent was evaporated in vacuo and the residue was taken up in petroleum ether: washing with a mixed solvent of ethyl acetate 4:1 to remove N-methylaniline; the product obtained from the washing was recrystallized from chloroform to give a deep red solid (3.56g, 72%) as (Z) -2-nitroethen-1-amine.

The reaction equation of this step is as follows:

(3) (Z) -2-nitroethen-1-amine (3.5g, 40.0mmol) was added to 160mL CH₂Cl₂Then triethylamine TEA (22.2mL, 160.0mmol) was added, stirred for 15 minutes, then cooled to 0 deg.C and phthaloyl chloride (5.8mL, 40.0 mmol; available from Energy Chemical) was added all at once at 0 deg.C; heating the obtained solution to room temperature, and then stirring and reacting for 48 hours at room temperature; after completion of the reaction, the solvent was distilled off under reduced pressure to give the crude product as a dark yellow solid, which was then washed with distilled water and 10mL of CH, respectively₂Cl₂Washing gave the product (7.8g, 90%) as a pale yellow solid, which was (E) -2- (2-nitrovinyl) isoindoline (I).

The reaction equation of this step is as follows:

preparation example 6

A process for the preparation of 3-pentyl trichloroacetimidate (VI) comprising the steps of:

3-pentanol (4.4g, 50.0mmol) was added to 10mL anhydrous Et₂In O, obtaining an ether solution of 3-pentanol; adding NaH (0.2g, 8.3mmol) into 8mL of diethyl ether under an argon atmosphere to obtain NaH diethyl ether suspension, and then dropwise adding the diethyl ether solution of 3-pentanol into the NaH diethyl ether suspension for 10 min; after the dropwise addition is finished, stirring for 10min at room temperature to obtain a mixed solution; under the condition of argon atmosphere and-5 ℃, dropwise adding the mixed solvent into a diethyl ether (10mL) solution of trichloroacetonitrile (7.5mL, 75.0mmol) for 20 min; after the dropwise addition is finished, heating the reaction system to room temperature, and stirring for reaction for 2 hours; after completion of the reaction, the solvent was distilled off under reduced pressure, and then 10mL of a mixed solvent of MeOH and n-hexane (MeOH/n-hexane volume ratio: 1:19) was added to the obtained residue, and stirred for 1min to precipitate out, which was filtered off and washed with cold n-hexane, and the filtrate was collected and the solvent was distilled off under reduced pressure to obtain 3-pentyltrichloroacetimidate (8.0g, 68%) as a light brown oil.

The reaction equation is as follows:

the hydrogen bond catalysts III-1, III-2, III-4, III-5, (E) -2- (2-nitrovinyl) isoindoline (I) and the trichloroacetonitrile intermediate 3-pentyltrichloroacetimidate (VI) used in the examples were each prepared from preparation examples 1 to 6.

Example 1

A new synthesis method of oseltamivir comprises the following steps:

(1) adding (E) -2- (2-nitrovinyl) isoindoline (I) (1.08g, 5.0mmol) into a 100mL round-bottom flask, vacuumizing and filling argon for protection, and adding 40mL of anhydrous dichloromethane for dissolving; dissolving ethyl pyruvate (II) (0.87g, 7.5mmol) in 10mL of anhydrous dichloromethane, dropwise adding the solution into a reaction system under the condition of stirring, adding a hydrogen bond catalyst 1- ((1R,2R) -2-aminocyclohexyl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea (III-1) (192.0mg, 0.5mmol) into the reaction system after dropwise adding, adding an acid catalyst 1 acetic acid (81.0uL, 1.5mmol), stirring and reacting for 18h at 25 ℃, and detecting the reaction completion through thin layer chromatography; then, the reaction solution is decompressed and distilled to remove the solvent, the obtained product is purified by silica gel (200-300 meshes) column chromatography, and the eluent is petroleum ether: ethyl acetate: dichloromethane ═ 4:1:1 mixed solvent to give ethyl 4- (1, 3-dioxoisoindol-2-yl) -5-nitro-2-oxopentanoate (iv) as a white solid (yield based on starting material converted, 726.0mg, 68%) and (E) -2- (2-nitrovinyl) isoindoline (i) was recovered (410.0mg, 38%).

The characterization data of the obtained product IV are as follows:

¹H-NMR(CDCl₃,400MHz):δ1.36(t,J＝7.2Hz,3H),3.52-3.72(m,2H),4.32(q,J＝7.2Hz,2H),4.82(dd,J＝13.2,4.8Hz,1H),5.12(dd,J＝13.2,9.6Hz,1H),5.44-5.52(m,1H),7.76(dd,J＝5.6,2.8Hz,2H),7.86(dd,J＝5.6,3.2Hz,2H)；

13C-NMR(CDCl₃,100MHz):δ13.9,39.1,43.8,53.5,63.2,74.4,76.7,123.8,131.3,134.6,159.7,167.3,189.9；

HRMS(ESI):Cacl.M:334.0801,[M+H]⁺:335.0879,Found:335.0874。

(2)4- (1, 3-Dioxoisoindol-2-yl) -5-nitro-2-oxopentanoic acid ethyl ester (IV) (501.0mg, 1.5mmol) was placed in a 100mL round-bottomed flask, evacuated and filled with argon, dissolved by adding 30mL of anhydrous tetrahydrofuran, and (formylmethylene) triphenylphosphine (547.0mg, 1.8mmol) was added to the reaction system in two portions in average with stirring, with an interval of 5min, and then stirred at 25 ℃ for 12h, and the completion of the reaction was detected by thin layer chromatography. After the reaction is finished, the reaction solution is decompressed and distilled to remove the solvent, and is purified by silica gel (200-300 meshes) column chromatography, and the eluent is petroleum ether: ethyl acetate 4:1 mixed solvent to give a mixture of the pair of white epimers ethyl (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylate (v) and ethyl (3S,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylate (v-1) (389.0mg, 72%); and then separating epimers by silica gel (200-300 meshes) column chromatography, wherein the eluent is chloroform: ethyl acetate 10:1 mixed solvent to give (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylic acid ethyl ester (v), a light yellow solid (188.0mg, 33%, 78% ee), and the epimer, pale white solid (3S,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylic acid ethyl ester (v-1) (201.0mg, 39%, 77% ee).

Characterization data for the resulting ethyl (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylate (V) are:

¹H-NMR(CDCl₃,400MHz):δ1.30(t,J＝7.2Hz,3H),1.50-2.10(brs,1H),2.82(dd,J＝18.0,6.0Hz,2H),3.13-3.23(m,1H),4.23(q,J＝7.2Hz,2H),4.85-4.89(m,1H),4.98(td,J＝11.3,6.1Hz,1H),5.12-5.18(m,1H),5.55(dd,J＝12.0,8.8Hz,1H),6.87(s,1H),7.76(dd,5.5,3.0Hz,2H),7.86(dd,J＝5.4,3.0Hz,2H)；

¹³C-NMR(CDCl₃,100MHz):δ14.15,28.1,47.2,61.5,70.1,77.2,88.0,123.8,129.5,131.3,134.6,136.7,164.8；

HRMS(ESI):Cacl.M：360.0958，[M+H]⁺:361.1036,Found:361.1038。

characterization data for ethyl (3S,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylate (v-1):

¹H-NMR(CDCl₃,400MHz):δ1.30(t,J＝7.1,3H),2.53-2.62(brs,1H),2.94-3.00(m,2H),4.23(q,J＝7.1,2H),5.06-5.13(brs,1H),5.20-5.30(m,1H),5.74(dd,J＝12.1,4.1,1H),6.99-7.03(m,1H),7.75(dd,J＝8.5,3.1,2H),7.86(dd,J＝5.5,3.1,2H)；

¹H-NMR(DMSO-d₆,400MHz):δ1.23(t,J＝7.1,3H),2.73(ddd,J＝17.2,11.0,1.7,1H),2.83(dd,J＝18.1,6.0,1H),4.16(q,J＝7.1,2H),4.87-4.93(m,1H),5.05(td,J＝11.1,6.2Hz,1H),5.75(dd,J＝12.0,4.5Hz,1H),6.23(d,J＝2.9Hz,1H),6.84(dd,J＝5.3,1.8Hz,1H),7.84-7.94(m,4H)；

¹³C-NMR(DMSO-d_6,100MHz):14.0,28.3,43.0,60.8,65.0,84.3,123.4,129.6,131.0,134.8,135.4,165.0,167.5；

HRMS(ESI):Cacl.M:360.0958,[M+H]⁺:361.1036,Found:361.1038。

(3) ethyl (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylate (V) (108.0mg, 0.3mmol) was charged into a 50mL two-necked round-bottom flask, and a spherical condenser was added, after which the whole reaction system was evacuated under argon and dissolved by adding 15mL of anhydrous dichloromethane; directly adding a newly prepared trichloroacetonitrile intermediate (VI) (1.74g,7.5mmol) into a reaction system, heating to 50 ℃, starting reflux, adding trifluoromethanesulfonic acid (450.0mg, 3.0mmol) into the reaction system after the reflux is started, monitoring the reaction condition of the compound of the formula V by using thin-layer chromatography after reacting for 2h, supplementing the trichloroacetonitrile intermediate (VI) (1.74g,7.5mmol), monitoring the reaction condition by using a thin layer, and monitoring that the compound of the formula V is completely consumed after 6.5 h. After the reaction is finished, cooling the reaction system to 0 ℃, adding 15mL of saturated sodium bicarbonate solution under the stirring condition to quench the reaction, filtering to remove solid impurities, extracting the filtrate with dichloromethane (10mL multiplied by 4), drying the obtained dichloromethane phase with anhydrous sodium sulfate, then distilling under reduced pressure to remove the solvent, and purifying the obtained product by silica gel column chromatography (silica gel 200-300 meshes, and eluent is a mixed solvent with the volume ratio of petroleum ether to ethyl acetate being 10: 1) to obtain a light yellow oily substance (86.0mg, 71%);

the pale yellow oil was mixed with 10% of a compound of formula A (by¹H NMR for corresponding identification of structure and ratio) of the productAnd (4) crystallizing the product.

Characterization data for the pale yellow oil are as follows:

¹H-NMR(CDCl₃,400MHz):δ0.80(t,J＝7.4Hz,3H),0.93(t,J＝7.4Hz,3H),1.30(t,J＝7.1Hz,3H),1.40-1.50(m,4H),2.79(dd,J＝17.7,6.0Hz,1H),3.12-3.23(m,1H),3.34(quintet,J＝11.5Hz,1H),4.23(q,J＝7.1Hz,2H),4.85-4.90(m,1H),4.95(td,J＝11.3,6.1Hz,1H),5.55(dd,J＝12.1,8.9Hz,1H),6.86(s,1H),7.75(dd,J＝5.4,3.1Hz,2H),7.86(dd,J＝5.5,3.0Hz,2H)；

¹³C-NMR(CDCl₃,100MHz):δ9.4,14.2,26.2,28.1,47.7,61.4,75.2,82.5,87.1,123.8,129.0,131.4,134.5,136.0,165.0

HRMS(ESI):Cacl.430.1740,[M+H]⁺:431.1818,[M+NH₄]⁺:448.2084,Found:431.1820,448.2079。

the above data indicate that the pale yellow oil is ethyl (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -4-nitro-3- (pentyl-3-yloxy) cyclohex-1-ene-1-carboxylate (VII) with the isomer ethyl (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -4-nitro-3- (pentyl-2-yl) oxy) cyclohex-1-ene-1-carboxylate (A).

(4) To an oven dried 10mL Schlenk tube was added a mixture (80.0mg, 0.186mmol) of 90% ethyl (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -4-nitro-3- (pentyl-3-yloxy) cyclohex-1-ene-1-carboxylate (VII) and 10% ethyl (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -4-nitro-3- (pentyl-2-yl) oxy) cyclohex-1-ene-1-carboxylate (A), evacuated under argon, 3mL volume ratio THF: h₂Adding stannous chloride dihydrate (420.0mg, 1.86mmol) into a mixed solvent with O being 8:1 under magnetic stirring, and reacting for 24h at 50 ℃; after the reaction was completed, the reaction solution was cooled to room temperature, the reaction was quenched with 15mL of saturated sodium bicarbonate solution, filtered, the resulting filtrate was separated, the aqueous phase was extracted with ethyl acetate (4X 40mL), the ethyl acetate phases were combined, and ethyl acetate was addedThe phases were dried over anhydrous sodium sulfate and the solvent was removed to give the reduced product.

Adding all the prepared reduction products into a dried 10mL Schlenk tube, vacuumizing, filling argon, adding 2mL of anhydrous dichloromethane to dissolve the reduction products, adding triethylamine (56.5mg,0.558mmol), cooling the reaction system to-10 ℃, dropwise adding new distilled anhydrous acetyl chloride (36.5mg,0.465mmol) under magnetic stirring, heating to room temperature after the addition is finished, reacting for 8h, and monitoring the completion of the reaction by using thin layer chromatography. After the reaction was completed, 15mL of a saturated sodium bicarbonate solution was added to the system to quench the reaction, the reaction was filtered, the filtrate was separated, the aqueous phase was extracted with dichloromethane (10mL × 3), then the dichloromethane phases were combined, the dichloromethane phase was dried over anhydrous sodium sulfate, the solvent was removed, and the obtained product was purified by silica gel column chromatography (silica gel 200-300 mesh, eluent was a mixed solvent of n-hexane: ethyl acetate 3:1 in volume ratio) to obtain a white oily substance, namely ethyl (viii) 3R,4R,5S) -4-acetylamino-5- (1, 3-dioxoisoindol-2-yl) -3- (pentyl-3-yloxy) cyclohex-1-ene-1-carboxylate (43.0mg, 53%)

The characterization data of the obtained ethyl (3R,4R,5S) -4-acetylamino-5- (1, 3-dioxoisoindol-2-yl) -3- (pentyl-3-yloxy) cyclohex-1-ene-1-carboxylate (VIII) are as follows:

¹H-NMR(CDCl₃,400MHz):δ0.87(t,J＝7.4Hz,3H),0.92(t,J＝7.4Hz,3H),1.28(t,J＝7.1Hz,3H),1.47-1.56(m,4H),1.76(s,3H),2.69(dd,J＝17.5,5.6Hz,1H),3.13-3.25(m,1H),3.31-3.39(m,1H),4.21(q,J＝6.5Hz,2H),4.35-4.42(m,1H),4.52(d,J＝9.2Hz,1H),4.86(td,J＝11.3,5.6Hz,1H),5.52(d,J＝7.9,1H),6.84(m,1H),7.72(dd,J＝5.5,3.0Hz,2H),7.83(dd,J＝5.2,3.1Hz,2H)；

¹³C-NMR(CDCl₃,100MHz):δ9.3,9.7,14.2,23.3,25.7,26.4,28.4,48.3,53.8,60.1,74.7,81.8,123.4,129.1,134.1,138.1,165.9,168.2,170.3；

HRMS(ESI):Cacl.442.2104,[M+H]⁺:443.2182,[M+Na]⁺:465.2002,Found:443.2179,465.1999。

(5) (3R,4R,5S) -4-acetamido-5- (1, 3-dioxo-isoindol-2-yl) -3- (pentyl-3-yloxy) cyclohexyl-1-ene-1-carboxylic acid ethyl ester (VIII) is subjected to deprotection reaction to prepare oseltamivir

Adding (3R,4R,5S) -4-acetamido-5- (1, 3-dioxo-isoindol-2-yl) -3- (pentyl-3-yloxy) cyclohexyl-1-ene-1-carboxylic acid ethyl ester (VIII) (22.0mg, 0.05mmol) into a 10mL dried Schlenk tube, vacuumizing and filling argon, adding 1mL absolute ethyl alcohol, adding 1mol/L hydrazine ethanol solution (250uL, 0.25mmol), reacting at 68 ℃ for 11 hours, after the reaction is finished, adding 10mL diethyl ether into the solution to separate out a precipitate, filtering to obtain a filtrate, discarding the precipitate, removing the solvent from the filtrate, and purifying the obtained product by silica gel column chromatography to obtain a yellow oily substance (13.0mg, 86%) which is oseltamivir; the silica gel used for silica gel column chromatography is 200-300 mesh silica gel, and the eluent is dichloromethane in volume ratio: methanol is a 5:1 mixed solvent.

The characterization data of the obtained product are as follows:

¹H-NMR(CDCl₃,400MHz):δ0.88(td,J＝7.4,4.3Hz,6H),1.30(t,J＝7.1Hz,3H),1.44-1.57(m,4H),1.72-1.88(brs,2H),2.04(s,3H),2.10-2.22(m,1H),2.74(dd,J＝17.8,5.0Hz,1H),3.23(td,J＝10.0,5.3Hz,1H),3.34(quintet,J＝11.3Hz,1H),3.54(m,1H),4.20(m,3H),5.74-5.84(brs,1H),6.79(s,1H)；

¹³C-NMR(CDCl₃,100MHz):δ9.3,9.6,14.2,23.7,25.7,26.3,33.5,49.2,58.9,60.9,74.9,81.7,129.5,137.6,166.4,171.0；

HRMS(ESI):Cacl.312.2049,[M+H]⁺:313.2127,Found:313.2131；

the light yellow oil was oseltamivir.

The total yield of oseltamivir obtained through the steps can reach 68% multiplied by 33% multiplied by 71% multiplied by 53% multiplied by 86% multiplied by 7.3%.

Example 2

A new synthesis of oseltamivir is as in example 1, except that: the hydrogen bonding catalyst was (R) -1- (2 '-amino- [1,1' -binaphthyl ] -2-yl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea (III-2) (0.5mmol) giving a yield of ethyl 4- (1, 3-dioxoisoindol-2-yl) -5-nitro-2-oxopentanoate (IV) of 11%.

Example 3

A new synthesis of oseltamivir is as in example 1, except that: the hydrogen bonding catalyst was N- [ (1R, 2R-2-amino-1, 2-diphenylethyl ] benzenesulfinamide (III-3) (0.5mmol) to give ethyl 4- (1, 3-dioxoisoindol-2-yl) -5-nitro-2-oxopentanoate (IV) in 15% yield.

Example 4

A new synthesis of oseltamivir is as in example 1, except that: the hydrogen bond catalyst was 1- ((1R,2R) -2-amino-1, 2-diphenylethyl) -3- (3, 5-bis (trifluoromethyl) phenyl) thiourea (iii-4) (0.5mmol) giving a yield of ethyl 4- (1, 3-dioxoisoindol-2-yl) -5-nitro-2-oxopentanoate (iv) of 15%.

Example 5

A new synthesis of oseltamivir is as in example 1, except that: the hydrogen bonding catalyst was 3- ((1R,2R) -amino-1, 2-diphenyldiethyl) -4- ((3, 5-bis (trifluoromethyl) phenyl) amino) cyclobut-3-ene-1, 2-dione (iii-5) (0.5mmol) giving a yield of ethyl 4- (1, 3-dioxoisoindol-2-yl) -5-nitro-2-oxopentanoate (iv) of 31%.

Example 6

A new synthesis of oseltamivir is as in example 1, except that: the addition amount of the ethyl pyruvate (II) in the step (1) is 6mmol, and the yield of the ethyl 4- (1, 3-dioxoisoindol-2-yl) -5-nitro-2-oxopentanoate (IV) is 41%.

Example 7

A new synthesis of oseltamivir is as in example 1, except that: in the step (2), adding 4- (1, 3-dioxoisoindol-2-yl) -5-nitro-2-oxopentanoic acid ethyl ester (IV) (108.0mg, 0.30mmol) into a 100mL round-bottom flask, vacuumizing and filling argon, dissolving the mixture by using 30mL anhydrous tetrahydrofuran, adding (formylmethylene) triphenylphosphine (110.0mg, 0.36mmol) into the reaction system in two batches under the stirring condition, and keeping the time interval for 5 min; the reaction mixture system was stirred at 50 ℃ for 4h, and the completion of the reaction was judged by thin layer chromatography to give ethyl (3R,4R,5S) -5- (1, 3-dioxoisoindol-2-yl) -3-hydroxy-4-nitrocyclohex-1-ene-1-carboxylate (V) (32.0mg, 30%, 90% ee).