Preparation method of oseltamivir and phosphate thereof

Abstract

The invention provides a preparation method of oseltamivir phosphate, which comprises the following steps: carrying out a deallylation reaction on a compound II to obtain an oseltamivir free alkali reaction solution, concentrating, dissolving in acetone, and reacting with phosphoric acid to obtain oseltamivir phosphate, the solvent is one or more of 1, 3-cyclohexanedione, 1, 3-cyclohexanedione, 1, 3-cyclopentanedione, Meldrum's acid, 5, 5-dimethyl-4-methyl-1, 3-cyclohexanedione, 1, 3-cyclohexanedione, 1, 3-cyclopentanedione, Meldrum's acid, and 5, 5-dimethyl-4-methyl-1, 3-cyclohexanedione. Compared with the prior art, the method has the advantages that materials with lower cost are used for replacing original expensive reagents to carry out allyl removal reaction, the molecular availability is improved, the cost is greatly reduced, the reaction system is clean, the next-step reaction can be directly carried out without post-treatment, the operation is simple and convenient, the cost advantage is obvious, a salifying system is optimized, crystallization is carried out in a reverse dropwise adding manner, and the yield is high. The obtained oseltamivir phosphate is large in particle, good in fluidity and convenient to prepare into a preparation.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and particularly relates to a method for preparing oseltamivir and its phosphate. Background Art

[0002] Oseltamivir phosphate is a neuramidase inhibitor. The drug was approved for marketing in China in 2001. It mainly acts on all links of influenza virus infection, preventing the replication of all clinically relevant influenza virus A or B strains, and is used to treat influenza A or B.

[0003] The chemical name of oseltamivir phosphate is (3R, 4R, 5S)-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester phosphate (1:1), and its structure is shown in the following formula:

[0004]

[0005] In recent years, influenza has been prevalent and the influenza virus has a very high mutation rate and is highly contagious. Currently, oseltamivir phosphate is considered to be an effective, safe and highly specific anti-influenza drug, so oseltamivir phosphate has a very broad commercial prospect.

[0006] There are many reports on the synthesis routes of oseltamivir phosphate, which are mainly divided into the azide synthesis route and the non-azide synthesis route. The azide synthesis route requires highly toxic substances such as sodium azide, and azides are extremely explosive, which brings great pressure to production safety. The non-azide synthesis route is commonly used in industry.

[0007] CN 100545145C discloses a synthetic route of oseltamivir phosphate, and the reaction formula is as follows:

[0008]

[0009] The steps of this route mainly include oxygen ring opening, nitrogen ring synthesis, nitrogen ring opening, acylation to form salts, de-tert-butylation, de-diallylation and then phosphate formation. Among them, the de-diallylation step uses ethanol as the reaction solvent, palladium acetate and triphenylphosphine as catalysts, and the expensive reagent 1,3-dimethylbarbituric acid (NDMBA) as the allyl transfer acceptor for the reaction.

[0010] CN101343241A discloses a preparation method and purification method of oseltamivir phosphate, which comprises firstly subjecting compound II, 1,3-dimethylbarbital, triphenylphosphine, palladium acetate and anhydrous ethanol to a heat-insulating reaction, then dropping the reaction solution into a reactor containing a phosphoric acid / ethanol solution at 50°C, stirring and reacting for 2 hours, cooling to -17-18°C, filtering after crystallization is completely completed, washing with acetone and n-heptane three times in sequence, and drying to obtain a crude oseltamivir phosphate product, then dissolving the crude oseltamivir phosphate product in anhydrous ethanol, heating to 60°C, adding activated carbon, continuing to heat to about 80°C, refluxing, filtering while hot, cooling the filtrate for crystallization, placing in a refrigerator overnight, filtering the next day, and drying to obtain a finished oseltamivir phosphate product with a yield of 89.15% and a purity of 99.77%.

[0011] CN 109438276A discloses a method for synthesizing oseltamivir, wherein 10% palladium on carbon is used as a catalyst and diethanolamine or ammonium formate is used as a hydrogen donor to carry out a de-diallyl reaction, wherein a large amount of palladium on carbon is used and the cost is high; after the de-diallyl reaction is completed, a brown solution is obtained after multiple post-treatments such as cooling, filtering, concentrating, acid dissolving, concentrating, extracting with methyl tert-butyl ether, adjusting the pH value with an ammonia solution, and extracting with ethyl acetate four times, and then the brown solution is salted with an ethanol solution of phosphoric acid to obtain a crude oseltamivir phosphate, and then the crude product is refined with an ethanol-water solvent to obtain a high-purity A-crystalline oseltamivir phosphate, and the post-treatment is complicated.

[0012] Since the prior art basically uses expensive reagent 1,3-dimethylbarbituric acid for desaccharylation reaction, and oseltamivir phosphate is crystallized in a mixed solvent, the generated oseltamivir phosphate finished product particles are small, and the filtration process is difficult and time-consuming. Therefore, it is very necessary to develop a preparation method for oseltamivir phosphate that is simple to operate, short in production time, and has cost advantages. Summary of the invention

[0013] In order to achieve the above object, the present invention adopts the following technical scheme: The present invention provides a method for preparing oseltamivir phosphate, comprising the following steps:

[0014] The compound II is subjected to deallylation reaction to obtain oseltamivir free base, the reaction solution is concentrated, dissolved in acetone, and then reacted with phosphoric acid to obtain oseltamivir phosphate;

[0015]

[0016] In some embodiments, the method comprises the following steps:

[0017] 1) concentrating the obtained oseltamivir free base reaction solution to dryness, and then dissolving it in acetone to obtain an acetone solution;

[0018] 2) adding the oseltamivir free base acetone solution obtained in step 1) dropwise to the acetone phosphate solution, and stirring to react;

[0019] 3) After the reaction is completed, the temperature is lowered to crystallize, and oseltamivir phosphate is obtained by filtration.

[0020] In some embodiments, the mass volume ratio of the amount of compound II to the amount of acetone is 1:5 to 1:10 g / mL;

[0021] In some embodiments, the mass concentration of the phosphoric acid is 30-50%, and the molar ratio of compound II to phosphoric acid is 1:1-1:1.1;

[0022] In some embodiments, the temperature of the dropwise addition and stirring reaction is 30 to 80° C., and the heat preservation reaction time after the dropwise addition is 1 to 4 hours;

[0023] In some embodiments, the temperature of the dropwise addition and stirring reaction is 40 to 50° C.; and the heat preservation reaction time after the dropwise addition is 1 to 2 hours.

[0024] In some embodiments, the cooling temperature is -20 to 10°C, preferably -5 to 5°C; the heat preservation and crystallization time is 1 to 6 hours, preferably 2 to 4 hours.

[0025] In some embodiments, the obtained oseltamivir phosphate has a particle size distribution of D10≤20 μm; D50: 60-100 μm; D90≥200 μm.

[0026] In some embodiments, the deallyl reaction is catalyzed by palladium acetate, triphenylphosphine and a nucleophile; wherein the nucleophile is selected from one or more of dimethyl malonate, diethyl malonate, 5,5-dimethyl-1,3-cyclohexanedione, 1,3-cyclohexanedione, 1,3-cyclopentanedione, McLaughlin's acid, and 5,5-dimethyl-4-methyl-1,3-cyclohexanedione;

[0027] In some embodiments, the nucleophile is 5,5-dimethyl-1,3-cyclohexanedione, Melchronic acid, or a mixture thereof;

[0028] In some embodiments, the deallyl reaction is carried out in an alcohol solvent;

[0029] In some embodiments, the mass ratio of the compound II, palladium acetate, triphenylphosphine and nucleophilic reagent is 1:0.001-0.002:0.03-0.05:0.4-0.8;

[0030] In some embodiments, the deallyl reaction temperature is 30 to 100° C., preferably 35 to 85° C.; the reaction time is 4 to 18 hours, preferably 5 to 12 hours;

[0031] In some embodiments, the mass volume ratio of the compound II to the alcohol solvent is 1:5 to 1:10 mg / mL;

[0032] In some embodiments, the alcohol solvent is selected from one or more of ethanol, methanol, and isopropanol, preferably ethanol.

[0033] Compared with the prior art, the present invention has the following positive technical effects:

[0034] 1. The preparation method provided by the present invention optimizes the salt-forming system and crystallizes by reverse dripping. The obtained oseltamivir phosphate has large particles and good fluidity, which is convenient for preparation. The filtration process is convenient and the time is short. The finished product has good fluidity. The obtained oseltamivir phosphate has good purity and high yield, and is suitable for large-scale industrial production.

[0035] 2. The preparation method provided by the present invention uses lower-cost materials instead of the original expensive reagents for deallyl reaction, thereby improving molecular utilization and greatly reducing costs. In addition, the reaction system is clean and can directly proceed to the next step of reaction without post-treatment. The operation is simple and the cost advantage is obvious. DETAILED DESCRIPTION

[0036] 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.

[0037] All ranges recited herein include those endpoints of the range between the two values ​​listed, whether stated or not, all values ​​recited herein include the expected experimental error, technical error, and instrument error for a given technique used to measure the value, and when the error degree is not stated, all values ​​recited herein include a range of ±10% of the stated value.

[0038] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0039] The reagents used in the present invention can all be purchased commercially.

[0040] The acetone phosphate solution used in the present invention is 30-50%, for example, 30%, 40%, 45%, 50% or any value or range therebetween.

[0041] Reference Example 1: Preparation of Compound II

[0042] Take 154kg of trifluoroacetic acid and put it into the reactor, add 48.5kg of (3R, 4R, 5S)-4-N-acetyl (1,1-dimethylethyl) amino-5-N, N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid ethyl ester (ie, oseltamivir acetylate), and stir to dissolve. Slowly heat to 35-55°C, keep warm and stir for about 6-8 hours. After the reaction, slowly cool to -20-0°C, add 90L of toluene to the reactor, add 40L of drinking water, stir evenly, and then add 30% sodium hydroxide solution to adjust the pH to 9-10. After adjustment, stir for about 1 hour and then let it stand for about 1 hour. After separation, add 70L of toluene to the water layer, stir for about 1 hour and let it stand for about 1 hour. After separation, combine the two organic layers, add 40L of drinking water, stir for about 1 hour and let it stand for about 1 hour. After separation, the organic layer was concentrated to dryness under reduced pressure at a temperature of 30-50° C., and then 70 L of ethanol was added to the concentrate, and the temperature was controlled at 30-50° C. and concentrated to dryness under reduced pressure to obtain compound II with a yield of 90% and a purity of 99.8%.

[0043] Embodiment 1:

[0044] Take 39.3kg (100mol) of compound II and put it into a reactor, add 280L of ethanol, stir and dissolve, add 21kg of 5,5-dimethyl-1,3-cyclohexanedione into the reactor, then replace the reactor with nitrogen three times, start stirring, add 39.3g of palladium acetate and about 1.35kg of triphenylphosphine into the reactor, then slowly heat to 75°C, keep stirring for about 10 hours, control by HPLC, when compound II is ≤0.5%, the reaction is complete; control the temperature of the reaction solution at 40-75°C and concentrate under reduced pressure for 6-10 hours, add 275L of acetone after concentration, and stir to dissolve. The solution was slowly cooled to 40-50° C., and then about 22.9 kg (105.16 mol) of 45% acetone phosphate was added dropwise. After the addition was completed, the temperature was maintained at 40-50° C. with stirring for about 1-2 hours, and then the temperature was slowly cooled to 0±5° C., and the temperature was maintained with stirring for about 2 hours. Then, the filter cake was rinsed three times with about 40 L*3 of 0±5° C. acetone. The filter cake was dried under reduced pressure at a controlled temperature of 30-40° C. for 12 hours to obtain oseltamivir phosphate with a yield of 80%, a purity of 99.9%, and a single impurity of <0.1%. The particle size distribution of oseltamivir phosphate was D10: 0.99 μm; D50: 78.7 μm, and D90: 298 μm.

[0045] Embodiment 2:

[0046] 39.3 kg of compound II was put into a reactor, 280 L of ethanol was added, and the mixture was stirred to dissolve. 21.62 kg of McBride's acid was added to the reactor, and then the reactor was replaced with nitrogen three times. 39.3 g of palladium acetate and about 1.35 kg of triphenylphosphine were added to the reactor, and then the temperature was slowly raised to 50 ° C, and the mixture was stirred for about 5 hours. The reaction was completed by controlling the reaction liquid at 40-75 ° C and concentrating under reduced pressure for 6-10 hours, and then 275 L of acetone was added and stirred to dissolve. The solution is slowly cooled to 40-50°C, and then about 22.9 kg of 45% acetone phosphoric acid is added dropwise. After the addition is completed, the temperature is maintained at 30-40°C and stirred for about 1 hour. The temperature is then slowly cooled to 0±5°C, and then maintained at 0±5°C and stirred for about 2 hours. The filter cake is then filtered to dryness. The filter cake is rinsed three times with about 40 L*3 of 0±5°C acetone. The filter cake is dried at 30-40°C under reduced pressure for 12 hours to obtain a white solid. The yield is 83%, the purity is 99.9%, and the single impurity is less than 0.1%. The particle size distribution of oseltamivir phosphate is D10: 1.8 μm, D50: 95.5 μm, and D90: 342 μm.

[0047] Comparative Example 1:

[0048] Repeat the method of Chinese patent CN 101343241A

[0049] Under nitrogen protection, 12g of ethyl (3R, 4R, 5S)-4-N-acetylamino-5-N, N-diallylamino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate, 5g of 1,3-dimethylbarbital, 0.3g of triphenylphosphine, 0.07g of palladium acetate and 55g of anhydrous ethanol were added to the reactor, and the mixture was stirred and heated to 35°C for 2 hours. Then, the hydrogenolysis reaction solution was added dropwise to another reactor containing 3.5g of phosphoric acid and 36.5g of anhydrous ethanol at 50°C, stirred for 2 hours, cooled to -17°C to -18°C, filtered after crystallization was complete, washed with acetone 20g*3 and n-heptane 20g*3 in sequence, and dried to obtain crude oseltamivir phosphate.

[0050] The crude oseltamivir phosphate obtained above and 270 g of anhydrous ethanol were added to the refining kettle, heated to 60°C, 1 g of activated carbon was added, and the mixture was heated to about 80°C and refluxed for 60 minutes for decolorization. The mixture was filtered while hot, and the filtrate was cooled to precipitate crystals, which were placed in the refrigerator overnight. The next day, the mixture was filtered and dried to obtain 10.0 g of oseltamivir phosphate finished product with a purity of 99.8%, wherein the particle size distribution of oseltamivir phosphate was

[0051] D10: 0.74μm; D50: 10.7μm; D90: 36.5μm.

[0052] 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 oseltamivir phosphate, characterized in that: The preparation method comprises the following steps: The compound II is subjected to deallylation reaction to obtain oseltamivir free base, the reaction solution is concentrated, dissolved in acetone, and then reacted with phosphoric acid to obtain oseltamivir phosphate; Compound II: oseltamivir free base.

2. The preparation method according to claim 1, characterized in that: The preparation method comprises the following steps: 1) concentrating the obtained oseltamivir free base to dryness, and then dissolving it in acetone to obtain an acetone solution; 2) adding the oseltamivir free base acetone solution obtained in step 1) dropwise to the acetone phosphate solution, and stirring to react; 3) After the reaction is completed, the temperature is lowered to crystallize, and oseltamivir phosphate is obtained by filtration.

3. The preparation method according to claim 2, characterized in that: The mass volume ratio of the amount of compound II to the amount of acetone in the step 1) is 1:5 to 1:10 g / mL.

4. The preparation method according to claim 2, characterized in that: In the step 2), the mass concentration of phosphoric acid is 30-50%, and the molar ratio of compound II to phosphoric acid is 1:1-1:1.

1.

5. The preparation method according to claim 2, characterized in that: In the step 2), after the dropwise addition is completed, the stirring reaction temperature is 30-80° C., preferably 40-50° C.; after the dropwise addition is completed, the heat preservation reaction time is 1-4 hours, preferably 1-2 hours.

6. The preparation method according to claim 2, characterized in that: In the step 3), the cooling temperature is -20 to 10°C, preferably -5 to 5°C; the heat preservation and crystallization time is 1 to 6 hours, preferably 2 to 4 hours.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The obtained oseltamivir phosphate particle size D10≤20μm; D50: 60-100μm; D90≥200μm.

8. The preparation method according to claim 1, characterized in that The deallyl reaction uses palladium acetate, triphenylphosphine and a nucleophilic agent as a catalyst; The nucleophilic agent is selected from one or more of dimethyl malonate, diethyl malonate, 5,5-dimethyl-1,3-cyclohexanedione, 1,3-cyclohexanedione, 1,3-cyclopentanedione, McBride's acid, and 5,5-dimethyl-4-methyl-1,3-cyclohexanedione; preferably 5,5-dimethyl-1,3-cyclohexanedione, McBride's acid or a mixture thereof.

9. The preparation method according to claim 8, characterized in that: The deallylation reaction is carried out in an alcohol solvent.

10. The preparation method according to claim 8, characterized in that: The mass ratio of the compound II, palladium acetate, triphenylphosphine and nucleophilic reagent is 1:0.001-0.002:0.03-0.05:0.4-0.

8.

11. The preparation method according to claim 8, characterized in that: The reaction temperature of the deallyl reaction is 30 to 100° C., preferably 35 to 85° C.; the reaction time is 4 to 18 hours, preferably 5 to 12 hours.

12. The preparation method according to claim 8, characterized in that: The mass volume ratio of the compound II to the alcohol solvent is 1:5 to 1:10 g / mL.

13. The preparation method according to claim 8, characterized in that: The alcohol solvent is selected from one or more of ethanol, methanol, and isopropanol, preferably ethanol.

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