CN109627180B - Preparation method of oseltamivir phosphate - Google Patents
Preparation method of oseltamivir phosphate Download PDFInfo
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- CN109627180B CN109627180B CN201811643110.4A CN201811643110A CN109627180B CN 109627180 B CN109627180 B CN 109627180B CN 201811643110 A CN201811643110 A CN 201811643110A CN 109627180 B CN109627180 B CN 109627180B
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- C07—ORGANIC CHEMISTRY
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- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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Abstract
The invention discloses a preparation method of oseltamivir phosphate, which comprises the steps of firstly, reacting an intermediate shown in a formula (IV) with palladium acetate, triphenylphosphine and N, N-dimethyl barbituric acid in a solvent, and removing allyl to obtain an intermediate shown in a formula (III); secondly, treating the intermediate shown in the formula (III) with acid, and removing tert-butyl to obtain oseltamivir free base shown in the formula (II); finally, the oseltamivir free base reacts with phosphoric acid in a solvent, and is crystallized and purified. According to the oseltamivir phosphate obtained by the method, the residual amounts of the main heavy metals such as palladium, arsenic, cadmium, cobalt, copper, mercury, lithium, nickel, lead, antimony, titanium, vanadium and the like are within a limit range, and accord with the ICH standard.
Description
Technical Field
The invention belongs to the field of preparation of medicinal products, and particularly relates to a preparation method of oseltamivir phosphate.
Background
Oseltamivir phosphate, as the only oral neuraminidase inhibitor in the world at present, has long been recognized as one of the most effective influenza prevention and treatment medicines in the world. It can be metabolized into neuraminidase inhibitor by human body, thereby inhibiting formation of new virus particle, reducing its transmission in human body, and relieving influenza symptom.
The structure of oseltamivir phosphate is shown as the formula (I):
at present, oseltamivir phosphate has a plurality of synthetic routes which are mainly divided into an azide synthetic route and a non-azide synthetic route. Most of the processes of the azide route have the defects of high energy consumption, dangerous operation, serious environmental pollution and the like. The non-azide route disclosed in patent CN1759093 is as follows:
removing tert-butyl from the Intermediate (IV) by trifluoroacetic acid to obtain an intermediate (V), removing allyl protecting group from the intermediate (V) by palladium acetate to obtain oseltamivir free base shown in a formula (II), and directly salifying with phosphoric acid to obtain oseltamivir phosphate. The method has the advantages of high yield, simple operation and good economic benefit, is suitable for industrial production, but has the defect that the obtained oseltamivir phosphate has excessive heavy metal element impurities.
Based on the consideration of drug safety, according to the relevant guideline of ICH, the residual and control of element impurities are more and more concerned in the drug research process at home and abroad. The heavy metal element residue in oseltamivir phosphate obtained by the method does not meet the relevant standard of ICH, and needs to be further improved.
Disclosure of Invention
The invention provides a preparation method of oseltamivir phosphate, which aims to overcome the technical problem of excessive residual of heavy metal element impurities in oseltamivir phosphate prepared by the prior art.
The method for preparing oseltamivir phosphate comprises the following steps:
(1) reacting the intermediate shown in the formula (IV) with palladium acetate, triphenylphosphine and N, N-dimethyl barbituric acid in a solvent, and removing allyl to obtain an intermediate shown in the formula (III);
(2) treating the intermediate shown in the formula (III) with acid, and removing tert-butyl to obtain oseltamivir free base shown in the formula (II);
(3) the oseltamivir phosphate shown in the formula (I) is obtained by reacting oseltamivir free base shown in the formula (II) with phosphoric acid in a solvent and carrying out crystallization and purification.
Wherein in the step (1), when the equivalent of the intermediate shown in the formula (IV) is 1eq, the equivalent of palladium acetate is 0.005-0.05eq, the equivalent of triphenylphosphine is 0.02-0.24eq, and the equivalent of N, N-dimethyl barbituric acid is 1.05-2.0 eq. The reaction temperature is 20-25 ℃. The reaction solvent is selected from one or mixture of dichloromethane, chloroform, methanol, ethanol, isopropanol and n-butanol, preferably ethanol.
In the step (2), the intermediate may be dissolved in an organic solvent, and then treated with an acid, wherein the organic solvent is selected from one or a mixture of dichloromethane, toluene, n-heptane, cyclohexane, n-hexane, methanol and ethanol, preferably dichloromethane or ethanol. The acid may be an organic or inorganic acid, preferably hydrochloric acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, and most preferably trifluoroacetic acid. The reaction temperature is 35-50 ℃.
In the step (3), the solvent is selected from an alcohol solvent such as methanol, ethanol, isopropanol, or a mixed solvent of an alcohol solvent and water, but is not limited thereto. The reaction temperature is from 0 to 100 ℃ and preferably from 45 to 50 ℃.
According to the oseltamivir phosphate obtained by the method, the residual amounts of the main heavy metals such as palladium, arsenic, cadmium, cobalt, copper, mercury, lithium, nickel, lead, antimony, titanium, vanadium and the like are within a limit range, and accord with the ICH standard.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The present invention will be described in detail below. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, which are provided for the purpose of making the disclosure more complete and complete. The reagents and starting materials used were all commercially available except for the preparation provided. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.
Example 1
A comparative example of oseltamivir phosphate was prepared using the method disclosed in CN 1759093.
Weighing 200g of the compound shown in the formula (IV), dissolving the compound in 300ml of dichloromethane, dripping the solution into 800ml of trifluoroacetic acid, and controlling the temperature to be less than or equal to 50 ℃ to react for 1 h. TLC monitored the end point, the solvent was concentrated under reduced pressure and taken up three times with toluene. Adding 800ml toluene and 800ml purified water into the concentrated solution, stirring vigorously for 30min, standing for layering, quenching and washing the organic layer with 400ml × 2 purified water, and combining the water layers. The aqueous layer was quenched with 200ml × 2 toluene. 800ml of methylene chloride was added to the aqueous layer, and the pH was adjusted to 9.0 with saturated aqueous Na2CO3 solution. Standing and layering. The aqueous layer was extracted with 400ml × 3 dichloromethane. And (4) combining dichloromethane layers, drying the dichloromethane layers by using anhydrous sodium sulfate, filtering the dichloromethane layers, and concentrating the obtained product to obtain an intermediate shown in the formula (V).
Under the protection of nitrogen, 800g of the compound shown in the formula (V) obtained above, 800g of absolute ethyl alcohol, 85.0g of N, N-dimethyl barbituric acid (0.54 mol), 1.01g of palladium acetate (0.0045 mol) and 4.73g of triphenylphosphine (0.018 mol) are sequentially added into a 2000ml reaction bottle, and after the addition is finished, the temperature is controlled to be 20-25 ℃, and the reaction is stirred for 2 hours. Cooling to 10-15 ℃, preserving heat for 30min, carrying out suction filtration, and concentrating the filtrate to obtain an oseltamivir free base crude product shown in the formula (II), wherein the yield is 88%, and the purity is 96.9%.
Dissolving the crude product of oseltamivir free base in 1000ml of absolute ethyl alcohol at room temperature, heating to 45-50 ℃, dripping 700ml of absolute ethyl alcohol over 60 minutes to dissolve a mixed solution of 60g of 85% phosphoric acid, and stirring for 45 minutes at 45-50 ℃; slowly cooling to 0 ℃ after 4.0h, maintaining the temperature to be minus 5-0 ℃, stirring for 60 minutes, carrying out suction filtration, rinsing the filter cake with 300ml of absolute ethyl alcohol, and carrying out suction drying. Vacuum drying (45-50 ℃) for 6 hours to obtain a white solid crude product of the formula (I). Dissolving the crude product of the formula (I) in a mixed solvent of 800ml of absolute ethyl alcohol and 140ml of purified water at room temperature, heating to 45-50 ℃, maintaining the temperature, continuously stirring for 60 minutes, quickly filtering while hot, and concentrating the mother liquor at 45 ℃ until solids are separated out; adding 800ml of absolute ethyl alcohol, and continuously concentrating at 45 ℃ to form paste; adding 800ml of absolute ethyl alcohol, heating, maintaining the temperature at 45-50 ℃, and continuing stirring for 60 minutes; adjusting the stirring speed to 75 revolutions per minute, slowly cooling, cooling to 0 ℃ after 2.5 hours, maintaining the temperature at minus 5-0 ℃, and stirring for 120 minutes; suction filtration, washing the filter cake with 300ml of absolute ethyl alcohol and suction drying. And (3) drying for 6 hours in vacuum at the temperature of 45-50 ℃ to obtain white solid oseltamivir phosphate of the formula (I).
The total yield is 63.5 percent, and the purity is 99.5 percent.
The results of the elemental impurities were as follows:
| elemental impurities | Limit (ppb) | The result of the detection |
| Palladium (II) | ≤1000 | 1316 |
| Arsenic (As) | ≤1500 | 9809 |
| Cadmium (Cd) | ≤200 | 7 |
| Cobalt | ≤500 | 211 |
| Copper (Cu) | ≤10000 | 3954 |
| Mercury | ≤300 | ND |
| Lithium ion source | ≤10000 | 101 |
| Nickel (II) | ≤2000 | 8354 |
| Lead (II) | ≤500 | 1163 |
| Antimony (Sb) | ≤10000 | 4030 |
| Titanium (IV) | ≤10000 | 1087 |
| Vanadium oxide | ≤1000 | 582 |
Wherein, heavy metal elements such as palladium, arsenic, nickel and lead are seriously out of the limits.
Example 2
Under the protection of nitrogen, a compound (179.5g, 0.40mol) shown in the formula (IV), 800g of absolute ethyl alcohol, 93.8g of N, N-dimethyl barbituric acid (0.60 mol), 0.45g of palladium acetate (0.002 mol), and 2.52g of triphenylphosphine (0.0096 mol) are sequentially added into a 2000ml reaction bottle, and after the addition, the temperature is controlled at 20-25 ℃, and the reaction is stirred for 2 hours. Cooling to 10-15 deg.C, maintaining the temperature for 30min, vacuum filtering, and concentrating the filtrate to obtain crude product of formula (III).
The crude product of the formula (III) is dissolved in 45ml of dichloromethane, added dropwise to 200ml of trifluoroacetic acid and reacted for 2h at the temperature of 35-40 ℃. Controlling the temperature of the reaction liquid to be less than or equal to 50 ℃, decompressing and concentrating the solvent, adding toluene and drying for three times. Adding 200ml toluene and 200ml purified water into the concentrated solution, stirring vigorously for 30min, standing for layering, quenching and washing the organic layer with 100ml × 2 purified water, and combining the water layers. 50 for aqueous layerml × 2 toluene quench wash. The aqueous layer was added with 200ml of dichloromethane and saturated Na2CO3The aqueous solution was adjusted to pH 9.0. Standing and layering. The aqueous layer was extracted with 100ml × 3 dichloromethane. And (3) combining dichloromethane layers, drying by anhydrous sodium sulfate, filtering and concentrating to obtain 30.3g of the crude product of the oseltamivir free base shown in the formula (II), wherein the yield is 97.0 percent, and the purity is 96.8 percent.
Dissolving the formula (II) in 240ml of absolute ethyl alcohol at room temperature, heating to 45-50 ℃, dripping a mixed solution of 150ml of absolute ethyl alcohol and 13.4g of 85% phosphoric acid over 60 minutes, and stirring for 45 minutes at 45-50 ℃; slowly cooling to 0 ℃ after 4.0h, maintaining the temperature to be minus 5-0 ℃, stirring for 60 minutes, carrying out suction filtration, rinsing the filter cake with 60ml of absolute ethyl alcohol, and carrying out suction drying. Vacuum drying (45-50 ℃) for 6 hours to obtain a white solid crude product of the formula (I). Dissolving the crude product of the formula (I) in a mixed solvent of 180ml of absolute ethyl alcohol and 30ml of purified water at room temperature, heating to 45-50 ℃, keeping the temperature, continuously stirring for 60 minutes, quickly filtering while hot, and concentrating the mother liquor at 45 ℃ until solids are separated out; adding 180ml of absolute ethyl alcohol, and continuously concentrating at 45 ℃ to form paste; adding 180ml of absolute ethyl alcohol, heating, maintaining the temperature at 45-50 ℃, and continuing stirring for 60 minutes; adjusting the stirring speed to 75 revolutions per minute, slowly cooling, cooling to 0 ℃ after 2.5 hours, maintaining the temperature at minus 5-0 ℃, and stirring for 120 minutes; suction filtration, rinsing the filter cake with 60ml of absolute ethanol and suction drying. And (3) drying for 6 hours in vacuum at the temperature of 45-50 ℃ to obtain white solid oseltamivir phosphate of the formula (I).
The total yield is 65.8 percent, and the purity is 99.8 percent.
The results of the elemental impurities were as follows:
| elemental impurities | Limit (ppb) | The result of the detection |
| Palladium (II) | ≤1000 | 6 |
| Arsenic (As) | ≤1500 | 40 |
| Cadmium (Cd) | ≤200 | 3 |
| Cobalt | ≤500 | 11 |
| Copper (Cu) | ≤10000 | 47 |
| Mercury | ≤300 | 22 |
| Lithium ion source | ≤10000 | 17 |
| Nickel (II) | ≤2000 | 38 |
| Lead (II) | ≤500 | 19 |
| Antimony (Sb) | ≤10000 | 83 |
| Titanium (IV) | ≤10000 | 54 |
| Vanadium oxide | ≤1000 | 8 |
The content of all heavy metals is within the limits.
Example 3
The reaction formula is the same as that of example 2.
Under the protection of nitrogen, the formula (IV) (44.9g, 0.10mol), 194g of absolute ethyl alcohol, 16.5g of N, N-dimethyl barbituric acid (0.105 mol), 0.115g of palladium acetate (0.005 mol) and 0.02mol of triphenylphosphine (5.25g, 0.02mol) are added into a 1000ml reaction bottle in sequence, and the temperature is controlled at 20-25 ℃ after the addition, and the reaction is stirred for 2 hours. Cooling to 10-15 deg.C, maintaining the temperature for 30min, vacuum filtering, and concentrating the filtrate to obtain crude product of formula (III).
The crude product of the formula (III) is dissolved in 45ml of dichloromethane, added dropwise to 200ml of trifluoroacetic acid and reacted for 2h at the temperature of 35-40 ℃. Controlling the temperature of the reaction liquid to be less than or equal to 50 ℃, decompressing and concentrating the solvent, adding toluene and drying for three times. Adding 200ml toluene and 200ml purified water into the concentrated solution, stirring vigorously for 30min, standing for layering, quenching and washing the organic layer with 100ml × 2 purified water, and combining the water layers. The aqueous layer was quenched with 50ml × 2 toluene. 200ml of dichloromethane were added to the aqueous layer, and the pH was adjusted to 9.0 with saturated aqueous Na2CO3 solution. Standing and layering. The aqueous layer was extracted with 100ml × 3 dichloromethane. The dichloromethane layers are combined, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 29g of oseltamivir shown in the formula (II), the yield is 94 percent, and the purity is 98.4 percent.
Dissolving the formula (II) in 240ml of absolute ethyl alcohol at room temperature, heating to 45-50 ℃, dripping a mixed solution of 150ml of absolute ethyl alcohol and 13g of 85% phosphoric acid over 60 minutes, and stirring for 45 minutes at 45-50 ℃; slowly cooling to 0 ℃ after 4.0h, maintaining the temperature to be minus 5-0 ℃, stirring for 60 minutes, carrying out suction filtration, rinsing the filter cake with 60ml of absolute ethyl alcohol, and carrying out suction drying. Vacuum drying (45-50 ℃) for 6 hours to obtain a white solid crude product of the formula (I). Dissolving the crude product of the formula (I) in a mixed solvent of 180ml of absolute ethyl alcohol and 30ml of purified water at room temperature, heating to 45-50 ℃, keeping the temperature, continuously stirring for 60 minutes, quickly filtering while hot, and concentrating the mother liquor at 45 ℃ until solids are separated out; adding 180ml of absolute ethyl alcohol, and continuously concentrating at 45 ℃ to form paste; adding 180ml of absolute ethyl alcohol, heating, maintaining the temperature at 45-50 ℃, and continuing stirring for 60 minutes; adjusting the stirring speed to 75 revolutions per minute, slowly cooling, cooling to 0 ℃ after 2.5 hours, maintaining the temperature at minus 5-0 ℃, and stirring for 120 minutes; suction filtration, rinsing the filter cake with 60ml of absolute ethanol and suction drying. And (3) drying for 6 hours in vacuum at the temperature of 45-50 ℃ to obtain white solid oseltamivir phosphate of the formula (I).
The total yield is 63.2 percent, and the purity is 99.7 percent.
The results of the elemental impurities were as follows:
| elemental impurities | Limit (ppb) | The result of the detection |
| Palladium (II) | ≤1000 | 11 |
| Arsenic (As) | ≤1500 | 27 |
| Cadmium (Cd) | ≤200 | 40 |
| Cobalt | ≤500 | 14 |
| Copper (Cu) | ≤10000 | 23 |
| Mercury | ≤300 | 5 |
| Lithium ion source | ≤10000 | 124 |
| Nickel (II) | ≤2000 | 28 |
| Lead (II) | ≤500 | 33 |
| Antimony (Sb) | ≤10000 | 112 |
| Titanium (IV) | ≤10000 | 97 |
| Vanadium oxide | ≤1000 | 34 |
The content of all heavy metals is within the limits.
Example 4
The reaction formula is the same as that of example 2.
Under the protection of nitrogen, the formula (IV) (44.9g, 0.10mol), 194g of absolute ethyl alcohol, 31g of N, N-dimethyl barbituric acid (0.20 mol), 0.449g of palladium acetate (0.002 mol) and 0.525g of triphenylphosphine (0.002 mol) are sequentially added into a 1000ml reaction bottle, and the temperature is controlled at 20-25 ℃ after the addition, and the reaction is stirred for 2 hours. Cooling to 10-15 deg.C, maintaining the temperature for 30min, vacuum filtering, and concentrating the filtrate to obtain crude product of formula (III).
The crude product of the formula (III) is dissolved in 45ml of dichloromethane, added dropwise to 200ml of trifluoroacetic acid and reacted for 2h at the temperature of 35-40 ℃. Controlling the temperature of the reaction liquid to be less than or equal to 50 ℃, decompressing and concentrating the solvent, adding toluene and drying for three times. Adding 200ml toluene and 200ml purified water into the concentrated solution, stirring vigorously for 30min, standing for layering, quenching and washing the organic layer with 100ml × 2 purified water, and combining the water layers. The aqueous layer was quenched with 50ml × 2 toluene. 200ml of dichloromethane were added to the aqueous layer, and the pH was adjusted to 9.0 with saturated aqueous Na2CO3 solution. Standing and layering. The aqueous layer was extracted with 100ml × 3 dichloromethane. The dichloromethane layers are combined, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 27.3g of oseltamivir shown in the formula (II), the yield is 87.5 percent, and the purity is 98.9 percent.
Dissolving the formula (II) in 240ml of absolute ethyl alcohol at room temperature, heating to 45-50 ℃, dripping a mixed solution of 150ml of absolute ethyl alcohol and 13g of 85% phosphoric acid over 60 minutes, and stirring for 45 minutes at 45-50 ℃; slowly cooling to 0 ℃ after 4.0h, maintaining the temperature to be minus 5-0 ℃, stirring for 60 minutes, carrying out suction filtration, rinsing the filter cake with 60ml of absolute ethyl alcohol, and carrying out suction drying. Vacuum drying (45-50 ℃) for 6 hours to obtain a white solid crude product of the formula (I). Dissolving the crude product of the formula (I) in a mixed solvent of 180ml of absolute ethyl alcohol and 30ml of purified water at room temperature, heating to 45-50 ℃, keeping the temperature, continuously stirring for 60 minutes, quickly filtering while hot, and concentrating the mother liquor at 45 ℃ until solids are separated out; adding 180ml of absolute ethyl alcohol, and continuously concentrating at 45 ℃ to form paste; adding 180ml of absolute ethyl alcohol, heating, maintaining the temperature at 45-50 ℃, and continuing stirring for 60 minutes; adjusting the stirring speed to 75 revolutions per minute, slowly cooling, cooling to 0 ℃ after 2.5 hours, maintaining the temperature at minus 5-0 ℃, and stirring for 120 minutes; suction filtration, rinsing the filter cake with 60ml of absolute ethanol and suction drying. And (3) drying for 6 hours in vacuum at the temperature of 45-50 ℃ to obtain white solid oseltamivir phosphate of the formula (I).
The total yield is 63.2 percent, and the purity is 99.5 percent.
The results of the elemental impurities were as follows:
| elemental impurities | Limit (ppb) | The result of the detection |
| Palladium (II) | ≤1000 | 20 |
| Arsenic (As) | ≤1500 | 18 |
| Cadmium (Cd) | ≤200 | ND |
| Cobalt | ≤500 | 26 |
| Copper (Cu) | ≤10000 | 110 |
| Mercury | ≤300 | ND |
| Lithium ion source | ≤10000 | 57 |
| Nickel (II) | ≤2000 | 9 |
| Lead (II) | ≤500 | 11 |
| Antimony (Sb) | ≤10000 | 49 |
| Titanium (IV) | ≤10000 | 38 |
| Vanadium oxide | ≤1000 | 16 |
The content of all heavy metals is within the limits.
Example 5
The reaction formula is the same as that of example 2.
Under the protection of nitrogen, the formula (IV) (44.9g, 0.10mol), 194g of absolute ethyl alcohol, 18.7g of N, N-dimethyl barbituric acid (0.12 mol), 0.157g of palladium acetate (0.0007 mol) and 0.024mol are sequentially added into a 1000ml reaction bottle, and after the addition is finished, the temperature is controlled to be 20-25 ℃, and the reaction is stirred for 2 hours. Cooling to 10-15 deg.C, maintaining the temperature for 30min, vacuum filtering, and concentrating the filtrate to obtain crude product of formula (III).
The crude product of the formula (III) is dissolved in 45ml of dichloromethane, added dropwise to 200ml of trifluoroacetic acid and reacted for 2h at the temperature of 35-40 ℃. Controlling the temperature of the reaction liquid to be less than or equal to 50 ℃, decompressing and concentrating the solvent, adding toluene and drying for three times. Adding 200ml toluene and 200ml purified water into the concentrated solution, stirring vigorously for 30min, standing for layering, quenching and washing the organic layer with 100ml × 2 purified water, and combining the water layers. The aqueous layer was quenched with 50ml × 2 toluene. 200ml of dichloromethane were added to the aqueous layer, and the pH was adjusted to 9.0 with saturated aqueous Na2CO3 solution. Standing and layering. The aqueous layer was extracted with 100ml × 3 dichloromethane. The dichloromethane layers are combined, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 30.1g of oseltamivir shown in the formula (II), the yield is 96.4 percent, and the purity is 97.5 percent.
Dissolving the formula (II) in 240ml of absolute ethyl alcohol at room temperature, heating to 45-50 ℃, dripping a mixed solution of 150ml of absolute ethyl alcohol and 13g of 85% phosphoric acid over 60 minutes, and stirring for 45 minutes at 45-50 ℃; slowly cooling to 0 ℃ after 4.0h, maintaining the temperature to be minus 5-0 ℃, stirring for 60 minutes, carrying out suction filtration, rinsing the filter cake with 60ml of absolute ethyl alcohol, and carrying out suction drying. Vacuum drying (45-50 ℃) for 6 hours to obtain a white solid crude product of the formula (I). Dissolving the crude product of the formula (I) in a mixed solvent of 180ml of absolute ethyl alcohol and 30ml of purified water at room temperature, heating to 45-50 ℃, keeping the temperature, continuously stirring for 60 minutes, quickly filtering while hot, and concentrating the mother liquor at 45 ℃ until solids are separated out; adding 180ml of absolute ethyl alcohol, and continuously concentrating at 45 ℃ to form paste; adding 180ml of absolute ethyl alcohol, heating, maintaining the temperature at 45-50 ℃, and continuing stirring for 60 minutes; adjusting the stirring speed to 75 revolutions per minute, slowly cooling, cooling to 0 ℃ after 2.5 hours, maintaining the temperature at minus 5-0 ℃, and stirring for 120 minutes; suction filtration, rinsing the filter cake with 60ml of absolute ethanol and suction drying. And (3) drying for 6 hours in vacuum at the temperature of 45-50 ℃ to obtain white solid oseltamivir phosphate of the formula (I).
The total yield is 64.3 percent, and the purity is 99.8 percent.
The results of the elemental impurities were as follows:
the content of all heavy metals is within the limits.
Example 6
The reaction formula is the same as that of example 2.
Under the protection of nitrogen, the formula (IV) (22.4kg, 49.9mol), 90kg of absolute ethyl alcohol, 7.79kg of N, N-dimethyl barbituric acid (49.9 mol), 0.11kg of palladium acetate (0.50 mol) and 4.99mol of triphenylphosphine (1.31kg, 4.99mol) are added into a 500L reaction bottle in sequence, and the temperature is controlled at 20-25 ℃ after the addition, and the reaction is stirred for 2 hours. Cooling to 10-15 deg.C, maintaining the temperature for 30min, vacuum filtering, and concentrating the filtrate to obtain crude product of formula (III).
The crude product of the formula (III) is dissolved in 22L of dichloromethane, added dropwise to 97L of trifluoroacetic acid and reacted for 2h at the temperature of 35-40 ℃. Controlling the temperature of the reaction liquid to be less than or equal to 50 ℃, decompressing and concentrating the solvent, adding toluene and drying for three times. Adding 90L toluene and 45L purified water into the concentrated solution, stirring vigorously for 30min, standing for layering, quenching and washing the organic layer with 45L × 2 purified water, and mixing the water layers. The aqueous layer was quenched with 22.5L × 2 toluene. 90L of dichloromethane was added to the aqueous layer, followed by addition of saturated Na2CO3The aqueous solution was adjusted to pH 9.0. Standing and layering. The aqueous layer was extracted with 45L × 3 dichloromethane. And (3) combining dichloromethane layers, drying by anhydrous sodium sulfate, filtering and concentrating to obtain 13.7kg of crude product of the oseltamivir free base shown in the formula (II), wherein the yield is 88.1 percent and the purity is 99.0 percent.
Dissolving the formula (II) in 110L of absolute ethyl alcohol at room temperature, heating to 45-50 ℃, dripping a mixed solution of 6.08kg of 85% phosphoric acid dissolved in 30L of absolute ethyl alcohol for more than 60 minutes, and stirring for 45 minutes at 45-50 ℃; slowly cooling to 0 ℃ after 4.0h, maintaining the temperature to be minus 5-0 ℃, stirring for 60 minutes, carrying out suction filtration, rinsing the filter cake with 27L of absolute ethyl alcohol, and carrying out suction drying. Vacuum drying (45-50 ℃) for 6 hours to obtain a white solid crude product of the formula (I). Dissolving the crude product of the formula (I) in a mixed solvent of 82L of absolute ethyl alcohol and 14L of purified water at room temperature, heating to 45-50 ℃, maintaining the temperature, continuously stirring for 60 minutes, quickly filtering while hot, and concentrating the mother liquor at 45 ℃ until solids are separated out; adding 82L of anhydrous ethanol, and continuously concentrating at 45 deg.C to obtain paste; adding 82L of absolute ethyl alcohol, heating, maintaining the temperature at 45-50 ℃, and continuing stirring for 60 minutes; adjusting the stirring speed to 75 revolutions per minute, slowly cooling, cooling to 0 ℃ after 2.5 hours, maintaining the temperature at minus 5-0 ℃, and stirring for 120 minutes; suction filtration, rinsing the filter cake with 27L of absolute ethanol and suction drying. And (3) drying for 6 hours in vacuum at the temperature of 45-50 ℃ to obtain white solid oseltamivir phosphate of the formula (I). The total yield is 64 percent, and the purity is 99.9 percent.
The results of the elemental impurities were as follows:
| elemental impurities | Limit (ppb) | The result of the detection |
| Palladium (II) | ≤1000 | 15 |
| Arsenic (As) | ≤1500 | 110 |
| Cadmium (Cd) | ≤200 | 17 |
| Cobalt | ≤500 | 7 |
| Copper (Cu) | ≤10000 | 55 |
| Mercury | ≤300 | ND |
| Lithium ion source | ≤10000 | 190 |
| Nickel (II) | ≤2000 | 40 |
| Lead (II) | ≤500 | 27 |
| Antimony (Sb) | ≤10000 | 38 |
| Titanium (IV) | ≤10000 | 154 |
| Vanadium oxide | ≤1000 | 39 |
The content of all heavy metals is within the limits.
Claims (9)
1. The preparation method of oseltamivir phosphate is characterized by comprising the following steps:
(1) reacting the intermediate shown in the formula (IV) with palladium acetate, triphenylphosphine and N, N-dimethyl barbituric acid in a solvent, and removing allyl to obtain an intermediate shown in the formula (III);
(2) treating the intermediate shown in the formula (III) with acid, and removing tert-butyl to obtain oseltamivir free base shown in the formula (II);
(3) the oseltamivir free base is reacted with phosphoric acid in a solvent and purified by crystallization.
2. The method according to claim 1, wherein in the step (1), when the intermediate equivalent represented by the formula (IV) is 1eq, the equivalent of palladium acetate is 0.005 to 0.05eq, the equivalent of triphenylphosphine is 0.02 to 0.24eq, and the equivalent of N, N-dimethylbarbituric acid is 1.05 to 2.0 eq.
3. The process of claim 1, wherein the reaction temperature in step (1) is 20-25 ℃.
4. The process of claim 1, wherein the reaction solvent of step (1) is selected from one or a mixture of dichloromethane, chloroform, methanol, ethanol, isopropanol, and n-butanol.
5. The process of claim 1, wherein the acid in step (2) is trifluoroacetic acid.
6. The method according to claim 1, wherein in the step (2), the intermediate represented by the formula (III) is dissolved in one or a mixture of solvents selected from the group consisting of dichloromethane, toluene, n-heptane, cyclohexane, n-hexane, methanol and ethanol, and then subjected to acid treatment.
7. The process of claim 1, wherein the reaction temperature in step (2) is 35-50 ℃.
8. The method of claim 1, wherein the solvent is selected from the group consisting of an alcoholic solvent and an alcoholic solvent mixed with purified water.
9. The method according to claim 8, wherein the solvent used for the crystallization purification is a mixed solvent of ethanol and water.
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| CN104447451A (en) * | 2014-11-13 | 2015-03-25 | 广东东阳光药业有限公司 | New preparation method of oseltamivir intermediate |
| CN108484467A (en) * | 2018-04-09 | 2018-09-04 | 华东理工大学 | A kind of preparation method of Oseltamivir acetylethyleneimine intermediate |
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| CN1759093A (en) * | 2003-03-13 | 2006-04-12 | 弗·哈夫曼-拉罗切有限公司 | Azide free process for preparing 1,2-diamino compounds |
| CN104447451A (en) * | 2014-11-13 | 2015-03-25 | 广东东阳光药业有限公司 | New preparation method of oseltamivir intermediate |
| CN108484467A (en) * | 2018-04-09 | 2018-09-04 | 华东理工大学 | A kind of preparation method of Oseltamivir acetylethyleneimine intermediate |
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