Preparation method of oseltamivir intermediate

Abstract

The invention provides a preparation method of an oseltamivir intermediate as shown in a formula II. The method comprises the following steps: step a) reacting a compound as shown in a formula I with diallylamine under the catalysis of zinc chloride to obtain a compound as shown in a formula II; # imgabs0 # after the reaction in the step b) is finished, carrying out post-treatment by using ammonia water at a certain temperature. According to the method, a large amount of excessive diallylamine does not need to be used, reaction byproducts are few, and particularly, formation of impurities can be effectively reduced and eliminated; in addition, inorganic salt residues can be effectively removed only by using a proper amount of ammonia water for post-treatment, the risk that heavy metal residues exceed the standard is reduced, and post-treatment is simple, convenient and effective.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a method for preparing an oseltamivir intermediate. Background Art

[0002] Oseltamivir phosphate, whose chemical name is (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate (1:1), is an orally effective influenza virus neuraminidase inhibitor. The drug was approved for marketing in China in 2001 and is clinically used to alleviate the symptoms of influenza, shorten the course of the disease, and reduce complications, especially for the prevention and treatment of avian influenza A. Its structural formula is shown below:

[0003]

[0004] The most economical synthesis route is reported in CN100545145C, which mainly includes oxygen ring opening, nitrogen ring synthesis, nitrogen ring opening, acylation to form salt, de-tert-butylation, de-diallylation and then phosphate formation, among which the nitrogen ring opening step is the most critical. The patent discloses that the nitrogen ring opening reaction can be carried out with diallylamine under the catalysis of nucleophilic reagents such as methanesulfonic acid, benzenesulfonic acid and 10-camphorsulfonic acid. Since this reaction step needs to be carried out under anhydrous conditions, the nucleophilic reagent needs to be subjected to high-temperature water separation treatment before the reaction, the reaction conditions are harsh, the operation is complicated and the reaction reagents are expensive.

[0005]

[0006] Patent CN114478290A discloses a method for preparing an oseltamivir intermediate shown in formula II, which comprises first reacting zinc chloride with an excess of diallylamine to form a complex, then reacting the complex with a compound of formula I to obtain an oseltamivir intermediate shown in formula II, and after the reaction is completed, the oseltamivir intermediate shown in formula II is treated with a citric acid aqueous solution, and then salted and purified to proceed to the next step reaction.

[0007] In view of the shortcomings and deficiencies of the prior art, it is necessary to develop a method for preparing an oseltamivir intermediate shown in formula II. Summary of the invention

[0008] In one aspect, the present invention provides a method for preparing an oseltamivir intermediate represented by formula II, the method comprising the following steps:

[0009] Step a) reacting the compound of formula I with diallylamine under the catalysis of zinc chloride to obtain a compound of formula II;

[0010]

[0011] Step b) After the reaction is completed, post-treatment is performed with aqueous ammonia at a certain temperature.

[0012] The inventors repeated the preparation method of CN114478290A and found that the amount of diallylamine used in this method was too large, and when the reaction solution was post-treated with citric acid aqueous solution, a large amount of flocculent precipitation would occur during stratification, which seriously affected the stratification operation and resulted in a large amount of inorganic salt residue in the product. The inorganic salt is difficult to remove, and there is a risk of excessive heavy metals in the finished product; and the prior art adds salt formation for purification, which is complicated to operate.

[0013] The inventors unexpectedly found that the reaction can proceed smoothly and with a high yield without using a large amount of excess diallylamine; and that the use of ammonia water treatment after the reaction can effectively remove the inorganic salt residue and is convenient to handle.

[0014] In addition, the inventors have also found that the method of the present invention can effectively reduce and eliminate the generation of impurities and improve the yield. The impurities are eliminated as shown in the following formula:

[0015]

[0016] In some embodiments, the solvent for the reaction in step a) is toluene; the molar ratio of the compound of formula I, diallylamine and zinc chloride is 1:1.05-4:0.5-1.5;

[0017] In some embodiments, the molar ratio of the compound of formula I, diallylamine and zinc chloride is 1:1.2-1.5:0.7-0.9;

[0018] In some embodiments, the reaction temperature of step a) is 100-120° C., and the reaction time is 10-24 h;

[0019] In some embodiments, the reaction temperature of step a) is 105-115° C., and the reaction time is 15-20 h.

[0020] In some embodiments, the concentration of aqueous ammonia in step b) is selected from 25 to 28%, wherein the molar ratio of the compound of formula I to the ammonia in aqueous ammonia is 1:3 to 4;

[0021] In some embodiments, the treatment temperature of step b) is 15-30°C.

[0022] In some embodiments, step a) is to first complex zinc chloride with diallylamine at a temperature of 20-30°C, then add the compound of formula I at a temperature of 20-40°C, and heat the temperature to 105-115°C for reaction.

[0023] In some embodiments, after the reaction in step b) is completed, the reaction solution is first cooled to 50-70°C, then toluene is added to dilute and stir, and the temperature is cooled to -5-5°C; then ice water and ammonia water are added respectively; after the addition is completed, the temperature is raised to 15-30°C and stirred; the layers are separated, the organic layers are combined, washed with water, and concentrated to obtain the oseltamivir intermediate shown in formula II.

[0024] Another aspect of the present invention provides an oseltamivir intermediate of formula II, wherein the content of impurity IMP-1 is eliminated to be less than 5% and the residual zinc ion content is less than 100 ppm.

[0025]

[0026] In some embodiments, the content of the eliminated impurity IMP-1 is less than 3.5% and the residual zinc ion content is 1-15 ppm.

[0027] Another aspect of the present invention provides use of the method of the present invention in the preparation of oseltamivir or a salt thereof;

[0028] In some embodiments, the treated oseltamivir intermediate of formula II does not need to be purified and is directly subjected to acetylation to obtain a compound of formula III.

[0029]

[0030] The acetylation is carried out under the action of NaOAc and Ac2O.

[0031] Compared with the prior art, the present invention has the following positive technical effects:

[0032] 1. The method for preparing the oseltamivir intermediate of formula II provided by the present invention does not require the use of a large amount of excess diallylamine, and has high reaction yield, high purity, few by-products, especially less impurities, low cost, and is suitable for large-scale industrial production.

[0033] 2. The preparation method of the oseltamivir intermediate shown in formula II provided by the present invention only needs to be post-treated with an appropriate amount of ammonia water to effectively remove inorganic salt residues, and the risk of excessive heavy metal residues is reduced; subsequently, the oseltamivir intermediate shown in formula II with low heavy metal residues can be obtained by layered extraction and water washing, and the post-treatment is effective and convenient, with less material loss. DETAILED DESCRIPTION

[0034] The following examples are used to further describe the specific embodiments of the present invention. The following examples are only used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0035] All ranges recited in the present invention include those endpoints of the range between two values, and no matter whether it is indicated, all values ​​recited in the present invention include the expected experimental error, technical error and instrument error of the given technology used to measure the value. When the error degree is not recorded, all values ​​recited in the present invention include the range of ± 10% of the recorded value.

[0036] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0037] Unless otherwise specified, the materials used in the present invention can be obtained through commercial channels.

[0038] The HPLC analysis method of the present invention for determining the oseltamivir intermediate represented by formula II and the oseltamivir intermediate represented by intermediate III: 1: Chromatographic conditions

[0039]

[0040] 2. Analytical method for determining zinc ion residues according to the present invention: ICP-MS

[0041] The oseltamivir intermediate of formula I was prepared by referring to the method of Example 1 of CN100545145C.

[0042] Embodiment 1:

[0043] Add 20L toluene and 3.52kg (25.83mol) zinc chloride to the reactor, control the temperature at 20-30°C, add 4.33kg (44.56mol) diallylamine, stir for about 0.5 hours, slowly control 20-40°C and slowly drop 10kg (32.32mol) of the intermediate of formula I oseltamivir obtained in the reference example, after the addition is completed, slowly heat up to 105-115°C, and stir for 20-22 hours starting from the temperature. After the reaction is completed, lower the material temperature to ≤70°C, add 7.5L toluene and stir for 30 minutes, continue to cool to -5-5°C and maintain the feed liquid temperature at -5-5°C, slowly drop about 12.9kg of ice water, and then slowly drop about 7.2kg (3.3eq) of 25% ammonia water. After the addition is completed, the temperature is slowly raised to 15-30°C, the layers are separated, and the aqueous layer is extracted with toluene twice, each time with about 9 L of toluene. The organic layers are combined and washed with about 9 L of water. The organic layer is concentrated by vacuum distillation at a temperature of 50-60°C until no liquid flows out to obtain an oily substance of about 12.5 kg of oseltamivir intermediate of formula II, with a yield of 95.1% and a purity of 94.9%, of which 3.1% of impurities are eliminated and the residual zinc ion content is 10 ppm.

[0044] Add 15.0 kg acetic anhydride (147 mol) and 3.6 kg sodium acetate (43.9 mol) to 12.5 kg of the above-mentioned oseltamivir intermediate of formula II, slowly heat to 105-115 ° C, keep warm and stir for 4-6 hours, after the reaction, cool to 25-35 ° C, add 37 kg n-heptane, stir evenly and cool to 0-10 ° C. Control 0-10° C. and slowly add sodium hydroxide solution (58 kg drinking water, 11.7 kg sodium hydroxide), stir to dissolve, adjust pH=9-12, separate layers, add 10 L n-heptane to extract the aqueous layer, separate layers, combine the organic layers, and wash with 12 kg water; separate layers, concentrate the organic layer under reduced pressure to an oily substance with substantially no fraction, add 60 kg acetone, stir to dissolve, cool to 5-15° C., slowly drop 6.4 kg 20% ​​hydrochloric acid acetone solution, after dropping, slowly lower the temperature in the autoclave to -10-0° C., keep warm and stir for 2-3 hours, centrifuge until almost no liquid flows out, rinse the wet product twice with acetone, each time with about 1.5 kg acetone, put the wet product into a drying drum, and vacuum dry it at 40-50° C. for 12 hours to obtain about 14.2 kg of a white solid oseltamivir intermediate represented by formula III, with a yield of 95%, a purity of 99.5%, and a residual zinc ion content of 3 ppm.

[0045] Embodiment 2:

[0046] Add 20L toluene and 3.52kg (25.83mol) zinc chloride to the reactor, control the temperature at 20-30°C, add 4.33kg (44.56mol) diallylamine, stir for about 0.5 hours, slowly control 20-40°C and slowly drop 10kg (32.32mol) of the oseltamivir intermediate of formula I obtained in the reference example, after the dropwise addition, slowly heat up to 100-110°C, and stir for 18-20 hours starting from the temperature. After the reaction is completed, lower the material temperature to ≤70°C, add 7.5L toluene and stir for 30 minutes, continue to cool to -5-5°C and maintain the feed liquid temperature at -5-5°C, slowly drop about 12.9kg of ice water, and then slowly drop about 7.2kg (3.3eq) of 25% ammonia water. After the dropwise addition, the temperature was slowly raised to 15-30°C, the layers were separated, and the aqueous layer was extracted with toluene twice, each time with about 9 L of toluene. The organic layers were combined and washed with about 9 L of water. The organic layer was concentrated by vacuum distillation at a temperature of 50-60°C until no liquid flowed out to obtain an oily substance of about 12.6 kg of the intermediate of formula II oseltamivir, with a yield of 96% and a purity of 95.2%, of which 2.9% of impurities were eliminated and the residual zinc ion content was 12 ppm.

[0047] 15.0 kg acetic anhydride (147 mol) and 3.6 kg sodium acetate (43.0 mol) were added to 12.6 kg of the above-mentioned oseltamivir intermediate of formula II, and the temperature was slowly raised to 105-115° C., and the mixture was stirred for 4-6 hours. After the reaction was completed, the temperature was lowered to 25-35° C., 37 kg of n-heptane was added, stirred evenly, and the temperature was lowered to 0-10° C. Control 0-10°C and slowly add sodium hydroxide solution (58kg drinking water, 11.7kg sodium hydroxide), stir to dissolve, adjust pH=9-12, separate layers, add 10L n-heptane to extract the aqueous layer once, combine the organic layers, add 12kg water to wash, separate layers, and concentrate the organic layer under reduced pressure to an oily substance with substantially no fraction, add 60kg ethyl acetate, stir to dissolve, and cool to 5-15°C; slowly add 10.7kg of 12% hydrochloric acid ethyl acetate solution; after the dropwise addition, slowly lower the temperature in the autoclave to -10-0°C, keep warm and stir for 2-3 hours, centrifuge until almost no liquid flows out, rinse the wet product twice with ethyl acetate, each time with about 1.5kg of ethyl acetate, put the wet product into a drying drum, and vacuum dry it at 40-50°C for 12 hours to obtain about 14.0kg of oseltamivir intermediate represented by white solid formula III, with a yield of 93%, a purity of 99.7%, and a residual zinc ion content of 2ppm.

[0048] Comparative Example 1: Refer to CN114478290A Example 1

[0049] Add 60 ml of toluene and 5.6 g (0.04 mol) of zinc chloride into a four-necked flask, seal with oil, and ventilate with nitrogen. Control the temperature at 20-30°C. Add 58.3 g (0.6 mol) of diallylamine, then slowly add 30.9 g (0.1 mol) of compound 1, slowly raise the temperature to 100-110°C, and stir for 18-20 hours starting from when the temperature reaches the starting time. After the reaction, the material temperature was lowered to ≤70°C, 30 ml of toluene was added and stirred for 30 minutes, the temperature was continued to be lowered to -5 to 5°C and the feed liquid temperature was maintained at -5 to 5°C, and a mixture of 19.1 g of citric acid and 173 g of water was slowly added dropwise, a large amount of flocculent precipitate appeared, and the layers were unclear. After the addition was completed, the temperature was raised to 15 to 30°C, the layers were separated, and the water layer was extracted with toluene three times, each time with about 40 ml of toluene. The organic layers were combined and washed once with about 20 ml of 30% sodium chloride solution. The organic layer was controlled at 50 to 60°C and concentrated by reduced pressure distillation until no liquid flowed out to obtain about 45 g of oily substance II oseltamivir intermediate, with a yield of 111%, a purity of 93%, and a residual zinc ion content of about 8%.

[0050] 45g of the above-mentioned oseltamivir intermediate of formula II was added with 51g (5eq) acetic anhydride and 12.0g sodium acetate (1.5eq), and the temperature was slowly raised to 105-115°C, and stirred for 4-6 hours. A large amount of compound II remained on the plate (about 10%), and the temperature was lowered to 25-35°C, 140g of n-heptane was added, stirred evenly, and the temperature was lowered to 0-10°C. Control 0-10° C. and slowly drop 10% sodium hydroxide solution to adjust pH=9-12, separate layers, extract the aqueous layer once with 45 ml of n-heptane, combine the organic layers, add 50 g of water to wash, separate layers, and concentrate the organic layer under reduced pressure to an oily substance with substantially no fraction, add 185 g of ethyl acetate, stir to dissolve, and cool to 5-15° C.; slowly drop 33 g of a 12% hydrochloric acid ethyl acetate solution; after dropping, slowly lower the temperature in the autoclave to -10-0° C., keep warm and stir for 2-3 hours, centrifuge until almost no liquid flows out, rinse the wet product twice with ethyl acetate, each time with about 5 kg of ethyl acetate, put the wet product into a drying drum, and vacuum dry it at 40-50° C. for 12 hours to obtain about 45.9 g of a white solid oseltamivir intermediate represented by formula III, with a yield of 85%, a purity of 95%, and a residual zinc ion content of about 7%.

[0051] Comparative Example 2: Refer to CN100545145C Example 2

[0052] Add 130 ml of toluene and 21.1 g (1.2 eq) of benzenesulfonic acid monohydrate into a four-necked flask, slowly heat up to 110±3°C, keep reflux and separate water until no obvious water flows out, slowly cool the feed liquid to 60-65°C, and concentrate to dryness under reduced pressure to obtain about 18.9 g of yellow-brown liquid, slowly heat up to 70-80°C and keep warm (solution A), and protect with nitrogen for treatment.

[0053] Control the temperature at 20-30°C, add 14.6g (1.5eq) of diallylamine, then slowly add 30.9g (1eq) of compound 1, then control 20-40°C, slowly drop the above solution A, then slowly heat up to 110-115°C, and stir for 4-6 hours when the temperature reaches the start time. After the reaction is completed, the material temperature is lowered to ≤70°C, 90ml of toluene is added and stirred for 30 minutes, and the temperature is continued to be lowered to -5-5°C and the feed liquid temperature is maintained at -5-5°C, and a mixture of 4.9g of sodium hydroxide and 62g of water is slowly added dropwise, and after the addition is completed, the temperature is raised to 15-30°C, and the layers are separated, and the water layer is extracted with toluene for 3 times, each time with about 40ml of toluene, and the organic layers are combined and washed once with 20ml of water, and the organic layer is controlled at 50-60°C and concentrated by reduced pressure distillation until no liquid flows out to obtain an oily substance of about 36.6g of formula II oseltamivir intermediate, with a yield of 90%, a purity of 90%, and 7% impurities are eliminated.

[0054] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art of the present invention may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.

Claims

1. A method for preparing an oseltamivir intermediate of formula II, characterized in that: The steps include: Step a) reacting the compound of formula I with diallylamine under the catalysis of zinc chloride to obtain the compound of formula II; Step b) after the reaction is completed, post-treating with aqueous ammonia at a certain temperature; 2. The preparation method according to claim 1, characterized in that: The solvent for the reaction in step a) is toluene; the molar ratio of the compound of formula I, diallylamine and zinc chloride is 1:1.05-4:0.5-1.5, preferably 1:1.2-1.5:0.7-0.

9.

3. The preparation method according to claim 1, characterized in that: The reaction temperature of step a) is 100-120° C., and the reaction time is 10-24 hours; preferably, the reaction temperature is 105-115° C., and the reaction time is 15-20 hours.

4. The preparation method according to claim 1, characterized in that: The concentration of the ammonia water in step b) is selected from 25-28%, and the molar ratio of the compound of formula I to the ammonia in the ammonia water is 1:3-4.

5. The preparation method according to claim 1, characterized in that: The certain temperature of step b) is 15-30°C.

6. The preparation method according to claim 1, characterized in that: The step a) is to firstly complex zinc chloride with diallylamine at a temperature of 20-30°C, then add the compound of formula I at a temperature of 20-40°C, and heat the temperature to 105-115°C to react.

7. The preparation method according to claim 1, characterized in that: After the reaction in step b) is completed, the reaction solution is first cooled to 50-70°C, then toluene is added to dilute and stir, and the temperature is cooled to -5-5°C; then ice water and ammonia water are added respectively; after the addition is completed, the temperature is raised to 15-30°C and stirred; the layers are separated, the organic layers are combined, washed with water, and concentrated to obtain the oseltamivir intermediate shown in formula II.

8. An oseltamivir intermediate of formula II, characterized in that: The content of impurity IMP-1 is less than 7% and the residual zinc ion is less than 100ppm. Preferably, the content of the eliminated impurity IMP-1 is less than 3.5% and the residual zinc ion content is 1 to 15 ppm; Further, the oseltamivir intermediate shown in formula II Prepared according to the method according to any one of claims 1 to 7.

9. A method for preparing a compound of formula III, characterized in that: Acetylation of the oseltamivir intermediate of formula II according to claim 8 to obtain a compound of formula III, 10. Use of the method according to any one of claims 1 to 7 or claim 8 in the preparation of oseltamivir or a salt thereof.

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