CN118791386A - A purification method and application of an important intermediate of oseltamivir phosphate - Google Patents

Abstract

The invention discloses a purification method and application of an important intermediate of oseltamivir phosphate, the purification method comprising the following steps: shikimic acid is added to thionyl chloride for esterification, the reaction solution is concentrated under reduced pressure at 40-60°C (vacuum ≤-0.085MPa) to obtain an oily substance, the oily substance concentrate is added to a dichloromethane-ethyl acetate-n-heptane mixed system, heated to dissolve, cooled to precipitate, filtered, dried, and a white solid is obtained; the application is to continue to react the dried intermediate I to obtain an intermediate V. The present invention uses intermediate I to concentrate the oily substance to crystallize to obtain intermediate I, and then obtains intermediate V through acetalization, mesyl protection, reduction, and ring closure. The method reduces the generation of impurities in the preparation process of intermediate V, improves the crystallization yield, and the quality of the obtained intermediate V is better than that of the intermediate V obtained without crystallization of intermediate I.

Description

A purification method and application of an important intermediate of oseltamivir phosphate

Technical Field

The invention belongs to the technical field of pharmaceutical compound preparation, and particularly relates to a purification method and application of an important intermediate of oseltamivir phosphate.

Background Art

5-(Pentan-3-yloxy)-7-oxo-bicyclo[4.1.0]hept-3-ene-3-carboxylic acid ethyl ester (Intermediate V) is a key core intermediate for preparing oseltamivir phosphate. The conventional synthesis method of Intermediate V is as follows:

Intermediate V is esterified by adding SM1 (shikimic acid) to thionyl chloride to obtain intermediate I, and then intermediate II is obtained through 3-pentanone acetal, and a protecting group is added to obtain intermediate III. Intermediate III is reduced with titanium tetrachloride to obtain intermediate IV. Intermediate IV is deprotected and ring-closed under alkaline conditions to obtain intermediate V. Due to the reversibility of the esterification reaction, the raw materials cannot be completely reacted, and intermediates II to IV are all oily. The residual SM1 will not only be passed on, but also participate in the reaction to derive impurities. The hydrogen chloride gas and sulfur dioxide produced by thionyl chloride cannot be quantified. Too much acid affects the reaction of intermediate II, resulting in a reduced yield of intermediate V.

SM1 passes as follows:

Summary of the invention

In order to solve the above problems, the present invention provides a purification method and application of an important intermediate of oseltamivir phosphate, wherein the intermediate I is concentrated and the oil is crystallized to obtain the intermediate I, and then the intermediate V is obtained by acetalization, mesyl protection, reduction, and ring closure. This method reduces the generation of impurities and improves the crystallization yield. The quality of the intermediate V obtained is better than that of the intermediate V obtained without crystallization of intermediate I, so as to achieve the effect of improving the utilization rate of raw materials, reducing costs, and ensuring quality. In order to achieve the above purpose, the main technical solutions provided by the present invention are as follows:

Shikimic acid is added with thionyl chloride for esterification, and the reaction solution is concentrated under reduced pressure at 40-60°C (vacuum ≤ -0.085MPa) to obtain an oily substance. The concentrated oily substance is added into a mixed system of dichloromethane-ethyl acetate-n-heptane, heated to dissolve, cooled to precipitate, filtered and dried to obtain a white solid, which is intermediate I.

The dried intermediate I is further reacted to obtain intermediate V;

The purity of the intermediate V thus prepared is ≥99.7%.

As a first aspect of the present invention, a method for purifying an important intermediate of oseltamivir phosphate is provided, wherein the intermediate is intermediate I, and the structural formula is:

The method comprises the following steps:

Step 1, adding thionyl chloride to a solution of shikimic acid to carry out an esterification reaction to prepare an intermediate I; after the reaction is completed, cooling;

Step 2: concentrate the reaction solution of intermediate I obtained in step 1 at 40-60°C under reduced pressure.

≤-0.085MPa, obtain concentrate and cool down;

Step 3, adding the concentrate obtained in step 2 into a mixed solvent system, heating to dissolve, and cooling to precipitate;

Step 4: filter and dry.

In an embodiment of the present invention, in step 1, the solution of shikimic acid is an ethanol solution of shikimic acid, and thionyl chloride is added dropwise to the ethanol solution of shikimic acid. After the addition is completed, the temperature is raised to 50-60° C. and stirred for reaction.

In the embodiment of the present invention, in step 2, the concentrate obtained by concentrating under reduced pressure is an oily substance.

Preferably, the mixed solvent system is a mixture of dichloromethane, ethyl acetate and n-heptane in a certain proportion, and none of the three can be missing.

Preferably, the ratio of the mixed solvent to the shikimic acid material is 2-10 mL/g, preferably 4-6 mL/g, more preferably 5 mL/g.

Preferably, the volume ratio of dichloromethane to ethyl acetate is 1:0.5 to 1:2, preferably 1:1.

Preferably, the volume ratio of dichloromethane to n-heptane is 1:1 to 1:5, preferably 1:3.

Preferably, in step 3, the system is heated to dissolve at a temperature of 30 to 50°C, preferably 35 to 45°C.

Preferably, in step 3, the cooling and crystallization temperature is 0 to 20°C, preferably 5 to 10°C.

Preferably, in step 3, the cooling and precipitation time is 1 to 10 hours, preferably 5 to 7 hours.

As a second aspect of the present invention, there is also provided an application of the purification method in the preparation of oseltamivir phosphate intermediate V, wherein the intermediate V is (3R, 4S, 5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid ethyl ester; specifically, the intermediate I obtained by drying in step 4 is further subjected to acetalization, mesyl protection, reduction, and ring closure to obtain (3R, 4S, 5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid ethyl ester.

Compared with the prior art, the present invention has the following beneficial effects:

The present invention adopts the method of heating and dissolving the concentrated oil of intermediate I in a mixed solvent system, cooling and crystallizing, and drying to obtain intermediate I, and then obtaining intermediate V through acetalization, mesyl protection, reduction, and ring closure. The method provides a specific mixed solvent composition. The inventor found in the research and development that dichloromethane, ethyl acetate, and n-heptane are indispensable and have a significant impact on the purity of the product; compared with the prior art, this treatment method significantly reduces the generation of impurities and improves the crystallization yield. The purity of the intermediate V obtained is higher than 99.7%, and the quality is better than that of the intermediate V obtained without crystallization of intermediate I; the reaction yield is higher than 80%, which significantly improves the production cost.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings in the specification, which constitute a part of the present invention, are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute improper limitations on the present invention.

Figure 1 is a liquid chromatogram of intermediate I in Comparative Example 1;

Fig. 2 is a liquid chromatogram of intermediate V of Comparative Example 1;

Figure 3 is a liquid chromatogram of intermediate I in Comparative Example 2;

Fig. 4 is a liquid chromatogram of intermediate V in Comparative Example 2;

Figure 5 is a liquid chromatogram of intermediate I in Comparative Example 3;

Figure 6 is a liquid chromatogram of intermediate V in Comparative Example 3;

Figure 7 is a liquid chromatogram of intermediate I in Example 1;

FIG8 is a liquid chromatogram of intermediate V in Example 1;

Figure 9 is a liquid chromatogram of intermediate I in Example 2;

Figure 10 is a liquid chromatogram of intermediate V in Example 2;

Figure 11 is a liquid chromatogram of intermediate I in Example 3;

Figure 12 is a liquid chromatogram of intermediate V in Example 3;

Figure 13 is a liquid chromatogram of intermediate I in Example 4;

Figure 14 is a liquid chromatogram of intermediate V in Example 4;

Figure 15 is a liquid chromatogram of intermediate Ⅰ in Example 5;

Figure 16 is a liquid chromatogram of intermediate V in Example 5;

Figure 17 is a liquid chromatogram of intermediate I in Example 6;

Figure 18 is a liquid chromatogram of intermediate V in Example 6;

Figure 19 is a liquid chromatogram of intermediate I in Example 7;

Figure 20 is a liquid chromatogram of intermediate V in Example 7;

Figure 21 is a liquid chromatogram showing the localization of intermediate I;

Figure 22 is a liquid chromatogram showing the localization of intermediate V.

DETAILED DESCRIPTION

It should be noted that the following detailed descriptions are exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those commonly understood by those skilled in the art to which the present invention belongs.

It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit exemplary embodiments according to the present invention. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprising" and/or "including" are used in this specification, it indicates the presence of features, steps, operations, devices, components and/or combinations thereof.

In the present application, the starting material (SM1) is shikimic acid.

Comparative Example 1: Preparation of Intermediate V by Conventional Method

At room temperature, SM1 (100.0 g, 574 mmol) and 600 mL of ethanol were added to a 1000 mL three-necked flask in sequence. After the addition was completed, thionyl chloride (34.16 g, 287 mmol) was added dropwise. After the addition was completed, the temperature was raised to reflux and stirred for 2 hours. The reaction was stopped and the mixture was concentrated under reduced pressure at 50°C (vacuum -0.09 MPa) to obtain Intermediate I.

HPLC was used for detection, chromatographic column (XB-C18, 4.6×250 mm, 5 μg); mobile phase A: 0.05% phosphoric acid aqueous solution (0.5 mL phosphoric acid, 1000 mL UP water), mobile phase B: acetonitrile; wavelength: 205 nm; flow rate: 1.0 mL/min.

Purity of intermediate I (HPLC%): 90.12%. The liquid phase spectrum is shown in Figure 1.

At room temperature, add the above intermediate I, triethyl orthoformate (118.00 g, 796 mmol), and 460 mL of anhydrous ethanol to a 1000 mL three-necked flask in sequence. After the addition is completed, cool to 0-10°C, add 3-pentanone (58.78 g, 682 mmol) dropwise, and stir for 3 hours. Stop the reaction, add triethylamine (14.39 g, 142 mmol) and stir, and concentrate under reduced pressure at 40°C (vacuum -0.09 MPa) to obtain intermediate II.

At room temperature, add the above intermediate II and ethyl acetate (600 mL) to a 2000 mL three-necked flask, stir and cool to -25 to -15 ° C, add methanesulfonyl chloride (85.51 g, 746 mmol) dropwise, then add triethylamine (116.21 g, 1148 mmol) dropwise, stir for 3 hours to stop the reaction. Add water (310 mL) dropwise, quench, stir, separate the liquids, extract the aqueous phase with ethyl acetate (300 mL), separate the liquids. Add 50.0 g of anhydrous sodium sulfate to the organic phase, dry it, filter it, and concentrate the filtrate at 50 ° C under reduced pressure (vacuum -0.09 MPa) to obtain intermediate III.

At room temperature, add the above intermediate III and dichloromethane (400mL) to a 2000mL three-necked flask, stir and cool to -45～-35℃, add triethylsilane (76.78g, 660mmol) dropwise, then add titanium tetrachloride (119.81g, 632mmol) + dichloromethane (800mL) dropwise for 9h, stir for 2h after the addition is complete, and stop the reaction. Add 0～10℃ water (100mL) dropwise, quench, stir, and separate. Add 10% sodium bicarbonate solution (200mL) dropwise to the organic phase, stir after the addition is complete, and separate. Add 50.0g of anhydrous sodium sulfate to the organic phase, dry it, filter, and concentrate the filtrate at 35℃ under reduced pressure (vacuum -0.09MPa) to obtain intermediate IV.

At room temperature, add the above intermediate IV, sodium bicarbonate (77.18 g, 919 mmol), anhydrous ethanol (400 mL), and water (900 mL) to a 2000 mL three-necked flask, heat to 50°C, stir for 2 h, and stop the reaction. Cool down, add n-heptane (1000 mL) at room temperature, stir, separate the liquids, add n-heptane (1000 mL) to the aqueous phase for extraction, separate the liquids, combine the organic phases, cool to -10 to 0°C, stir and crystallize for 2 h, and the obtained white filter cake is vacuum dried at 40 to 50°C for 8 h to obtain 46.21 g of intermediate V. Five-step yield: 31.64%. HPLC was used for detection, chromatographic column (XB-C18, 4.6×250 mm, 5 μg); mobile phase A: 0.05% phosphoric acid aqueous solution (0.5 mL phosphoric acid, 1000 mL UP water), mobile phase B: acetonitrile; wavelength: 205 nm; flow rate: 1.0 mL/min.

Purity of intermediate V (HPLC%): 99.08%. The liquid phase spectrum is shown in Figure 2.

Comparative Example 2: Intermediate I was purified with dichloromethane and n-heptane to prepare intermediate V

At room temperature, SM1 (100.0 g, 574 mmol) and 600 mL of ethanol were added to a 2000 mL three-necked flask in sequence. After the addition was completed, thionyl chloride (34.16 g, 287 mmol) was added dropwise, and the temperature was raised to 50-60°C and stirred for 6 hours. The reaction was stopped, and the concentrate was concentrated under reduced pressure at 50°C (vacuum -0.09 MPa) to obtain a concentrate, which was cooled to room temperature. The concentrate was mixed with 400 mL of a mixed solvent (160 mL of dichloromethane and 240 mL of n-heptane), heated to 40±5°C to dissolve, cooled to 5-10°C, stirred and crystallized for 6 hours, and the obtained white filter cake was vacuum dried at 40-50°C for 8 hours to obtain 95 g of intermediate I. The yield of intermediate I was 74.24%. The purity of intermediate I (HPLC%) was 96.28%. The liquid phase spectrum is shown in Figure 3.

Intermediate II to Intermediate V were prepared according to the method of Comparative Example 1 to obtain 84 g of Intermediate V. Five-step yield: 57.70%. Purity of Intermediate V (HPLC%): 97.43%. The liquid phase spectrum is shown in Figure 4.

Comparative Example 3: Intermediate I was purified with ethyl acetate and n-heptane to prepare intermediate V

At room temperature, SM1 (100.0 g, 574 mmol) and 600 mL of ethanol were added to a 2000 mL three-necked flask in sequence. After the addition was completed, thionyl chloride (34.16 g, 287 mmol) was added dropwise, and the temperature was raised to 50-60°C and stirred for 6 hours. The reaction was stopped, and the concentrate was concentrated under reduced pressure at 50°C (vacuum -0.09 MPa) to obtain a concentrate, which was cooled to room temperature. The concentrate was mixed with 400 mL of a mixed solvent (160 mL of ethyl acetate and 240 mL of n-heptane), heated to 40±5°C to dissolve, cooled to 5-10°C, stirred and crystallized for 6 hours, and the obtained white filter cake was vacuum dried at 40-50°C for 8 hours to obtain 87 g of intermediate I. The yield of intermediate I was 74.64%. The purity of intermediate I (HPLC%) was 95.23%. The liquid phase spectrum is shown in Figure 5.

Intermediate II to Intermediate V were prepared according to the method of Comparative Example 1 to obtain 77 g of Intermediate V. Five-step yield: 52.84%. Purity of Intermediate V (HPLC%): 98.24%. The liquid phase spectrum is shown in Figure 6.

Example 1: Purification of Intermediate I to Prepare Intermediate V (this Scheme)

At room temperature, SM1 (100.0 g, 574 mmol) and 600 mL of ethanol were added to a 2000 mL three-necked flask in sequence. After the addition was completed, thionyl chloride (34.16 g, 287 mmol) was added dropwise, and the temperature was raised to 50-60°C and stirred for 6 hours. The reaction was stopped, and the concentrate was concentrated under reduced pressure at 50°C (vacuum-0.09 MPa) to obtain a concentrate, which was cooled to room temperature. The concentrate was mixed with 360 mL of a mixed solvent (80 mL of dichloromethane, 40 mL of ethyl acetate, and 240 mL of n-heptane), heated to 40±5°C to dissolve, cooled to 5-10°C, stirred and crystallized for 6 hours, and the obtained white filter cake was vacuum dried at 40-50°C for 8 hours to obtain 113 g of intermediate I. Intermediate I was obtained. Yield: 97.32%. Purity of intermediate I (HPLC%): 99.02%. The liquid phase spectrum is shown in Figure 7.

Intermediate II to Intermediate V were prepared according to the method of Comparative Example 1 to obtain 120 g of Intermediate V. Five-step yield: 82.17%. Purity of Intermediate V (HPLC%): 99.07%. The liquid phase spectrum is shown in Figure 8.

Example 2: Purification of Intermediate I to Prepare Intermediate V (this Scheme)

At room temperature, SM1 (100.0 g, 574 mmol) and 600 mL of ethanol were added to a 2000 mL three-necked flask in sequence. After the addition was completed, thionyl chloride (34.16 g, 287 mmol) was added dropwise, and the temperature was raised to 50-60°C and stirred for 6 hours. The reaction was stopped, and the concentrate was concentrated under reduced pressure at 50°C (vacuum-0.09 MPa) to obtain a concentrate, which was cooled to room temperature. The concentrate was mixed with 480 mL of a mixed solvent (80 mL of dichloromethane, 160 mL of ethyl acetate, and 240 mL of n-heptane), heated to 40±5°C to dissolve, cooled to 5-10°C, stirred and crystallized for 6 hours, and the obtained white filter cake was vacuum dried at 40-50°C for 8 hours to obtain 109 g of intermediate I. Intermediate I was obtained. Yield: 93.88%. Purity of intermediate I (HPLC%): 99.52%. The liquid phase spectrum is shown in Figure 9.

Intermediate II to Intermediate V were prepared according to the method of Comparative Example 1 to obtain 118 g of Intermediate V. Five-step yield: 80.82%. Purity of Intermediate V (HPLC%): 99.91%. The liquid phase spectrum is shown in Figure 10.

Example 3: Purification of Intermediate I to Prepare Intermediate V (this Scheme)

At room temperature, SM1 (100.0 g, 574 mmol) and 600 mL of ethanol were added to a 2000 mL three-necked flask in sequence. After the addition was completed, thionyl chloride (34.16 g, 287 mmol) was added dropwise, and the temperature was raised to 50-60°C and stirred for 6 hours. The reaction was stopped, and the concentrate was concentrated under reduced pressure at 50°C (vacuum -0.09 MPa) to obtain a concentrate, which was cooled to room temperature. The concentrate was mixed with 240 mL of a mixed solvent (80 mL of dichloromethane, 80 mL of ethyl acetate, and 80 mL of n-heptane), heated to 40±5°C to dissolve, cooled to 5-10°C, stirred and crystallized for 6 hours, and the obtained white filter cake was vacuum dried at 40-50°C for 8 hours to obtain 107 g of intermediate I. Intermediate I was obtained. Yield: 92.15%. Purity of intermediate I (HPLC%): 99.39%. The liquid phase spectrum is shown in Figure 11.

Intermediate II to Intermediate V were prepared according to the method of Comparative Example 1 to obtain 117 g of Intermediate V. Five-step yield: 80.12%. Purity of Intermediate V (HPLC%): 99.87%. The liquid phase spectrum is shown in Figure 12.

Example 4: Purification of Intermediate I to Prepare Intermediate V (this Scheme)

At room temperature, SM1 (100.0 g, 574 mmol) and 600 mL of ethanol were added to a 2000 mL three-necked flask in sequence. After the addition was completed, thionyl chloride (34.16 g, 287 mmol) was added dropwise, and the temperature was raised to 50-60°C and stirred for 6 hours. The reaction was stopped, and the concentrate was concentrated under reduced pressure at 50°C (vacuum -0.09 MPa) to obtain a concentrate, which was cooled to room temperature. The concentrate was mixed with 560 mL of a mixed solvent (80 mL of dichloromethane, 80 mL of ethyl acetate, and 400 mL of n-heptane), heated to 40±5°C to dissolve, cooled to 5-10°C, stirred and crystallized for 6 hours, and the obtained white filter cake was vacuum dried at 40-50°C for 8 hours to obtain 114 g of intermediate I. Intermediate I was obtained. Yield: 98.18%. Purity of intermediate I (HPLC%): 99.07%. The liquid phase spectrum is shown in Figure 13.

Intermediate II to Intermediate V were prepared according to the method of Comparative Example 1 to obtain 121 g of Intermediate V. Five-step yield: 82.87%. Purity of Intermediate V (HPLC%): 99.45%. The liquid phase spectrum is shown in Figure 14.

Example 5: Purification of Intermediate I to Prepare Intermediate V (this Scheme)

At room temperature, SM1 (100.0 g, 574 mmol) and 600 mL of ethanol were added to a 2000 mL three-necked flask in sequence. After the addition was completed, thionyl chloride (34.16 g, 287 mmol) was added dropwise, and the temperature was raised to 50-60°C and stirred for 6 hours. The reaction was stopped, and the concentrate was concentrated under reduced pressure at 50°C (vacuum -0.09 MPa) to obtain a concentrate, which was cooled to room temperature. The concentrate was mixed with 400 mL of a mixed solvent (80 mL of dichloromethane, 80 mL of ethyl acetate, and 240 mL of n-heptane), heated to 40±5°C to dissolve, cooled to 5-10°C, stirred and crystallized for 6 hours, and the obtained white filter cake was vacuum dried at 40-50°C for 8 hours to obtain 111 g of intermediate I. Intermediate I was obtained. Yield: 95.23%. Purity of intermediate I (HPLC%): 99.25%. The liquid phase spectrum is shown in Figure 15.

Intermediate II to Intermediate V were prepared according to the method of Comparative Example 1 to obtain 124 g of Intermediate V. Five-step yield: 85.23%. Purity of Intermediate V (HPLC%): 99.89%. The liquid phase spectrum is shown in Figure 16.

Example 6: Purification of Intermediate I to Prepare Intermediate V (this Scheme)

At room temperature, SM1 (100.0 g, 574 mmol) and 600 mL of ethanol were added to a 2000 mL three-necked flask in sequence. After the addition was completed, thionyl chloride (34.16 g, 287 mmol) was added dropwise, and the temperature was raised to 50-60°C and stirred for 6 hours. The reaction was stopped, and the concentrate was concentrated under reduced pressure at 50°C (vacuum -0.09 MPa) to obtain a concentrate, which was cooled to room temperature. The concentrate was mixed with 600 mL of a mixed solvent (120 mL of dichloromethane, 120 mL of ethyl acetate, and 360 mL of n-heptane), heated to 40±5°C to dissolve, cooled to 5-10°C, stirred and crystallized for 6 hours, and the obtained white filter cake was vacuum dried at 40-50°C for 8 hours to obtain 112 g of intermediate I. Intermediate I was obtained. Yield: 96.46%. Purity of intermediate I (HPLC%): 99.36%. The liquid phase spectrum is shown in Figure 17.

Intermediate II to Intermediate V were prepared according to the method of Comparative Example 1 to obtain 123 g of Intermediate V. Five-step yield: 84.22%. Purity of Intermediate V (HPLC%): 99.79%. The liquid phase spectrum is shown in Figure 18.

Example 7: Purification of Intermediate 1 to Prepare Intermediate V (Present Scheme)

At room temperature, SM1 (3000g, 17.2mol) and ethanol (18L) were added to a 2000mL three-necked flask in sequence. After the addition was completed, thionyl chloride (1025g, 8.6mol) was added dropwise, and the temperature was raised to 50-60°C and stirred for 6 hours. The reaction was stopped, and the concentrate was concentrated under reduced pressure at 50°C (vacuum-0.09MPa) to obtain a concentrate, which was cooled to room temperature. The concentrate was mixed with 15L of a mixed solvent (3L of dichloromethane, 3L of ethyl acetate, 9L of n-heptane), heated to 40±5°C for dissolution, cooled to 5-10°C, stirred and crystallized for 6h, and the obtained white filter cake was vacuum dried at 40-50°C for 8h to obtain 3305g of intermediate I. Intermediate I was obtained. Yield: 94.89%. Purity of intermediate I (HPLC%): 99.35%. The liquid phase spectrum is shown in Figure 19.

Intermediate II to Intermediate V were prepared according to the method of Comparative Example 1 to obtain 3887 g of Intermediate V. Five-step yield: 88.72%. Purity of Intermediate V (HPLC%): 99.76%. The liquid phase spectrum is shown in Figure 20.

The localization liquid phase spectrum of intermediate I is shown in Figure 21.

The localization liquid phase spectrum of intermediate V is shown in Figure 22.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims (10)

1. A method for purifying an important intermediate of oseltamivir phosphate, wherein the intermediate is intermediate I, and the structural formula is: It is characterized by comprising the following steps: Step 1, adding thionyl chloride to a solution of shikimic acid to carry out an esterification reaction to prepare an intermediate I; after the reaction is completed, cooling; Step 2: concentrate the reaction solution of intermediate I obtained in step 1 at 40-60°C under reduced pressure. ≤-0.085MPa, to obtain a concentrate; Step 3, adding the concentrate obtained in step 2 into a mixed solvent system, heating to dissolve, and cooling to precipitate; Step 4: filter and dry. 2. The purification method according to claim 1, characterized in that in step 2, the concentrate obtained by concentrating under reduced pressure is an oily substance. 3. The purification method according to claim 1, characterized in that in step 3, the mixed solvent system is a mixed solvent of dichloromethane, ethyl acetate and n-heptane. 4. The purification method according to claim 3, characterized in that in step 3, the ratio of the mixed solvent to the shikimic acid material is 2-10 mL/g. 5. The purification method according to claim 3, characterized in that the volume ratio of dichloromethane to ethyl acetate is 1:0.5 to 1:2. 6 . The purification method according to claim 3 , characterized in that the volume ratio of dichloromethane to n-heptane is 1:1 to 1:5. 7. The purification method according to claim 1, characterized in that in step 3, the system is heated and dissolved at a temperature of 30 to 50°C. 8. The purification method according to claim 1, characterized in that in step 3, the cooling and crystallization temperature is 0 to 20°C. 9. The purification method according to claim 1, characterized in that in step 3, the temperature is lowered to precipitate crystals for 1 to 10 hours. 10. Use of the purification method according to any one of claims 1 to 9 in the preparation of oseltamivir phosphate intermediate V, characterized in that the intermediate V is (3R, 4S, 5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid ethyl ester; the intermediate I obtained by drying in step 4 is further reacted to obtain (3R, 4S, 5R)-3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid ethyl ester.