CN110698358A - Synthesis of continuous oseltamivir phosphate - Google Patents
Synthesis of continuous oseltamivir phosphate Download PDFInfo
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- CN110698358A CN110698358A CN201910970062.8A CN201910970062A CN110698358A CN 110698358 A CN110698358 A CN 110698358A CN 201910970062 A CN201910970062 A CN 201910970062A CN 110698358 A CN110698358 A CN 110698358A
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- C07—ORGANIC CHEMISTRY
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- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C—CHEMISTRY; METALLURGY
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- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Abstract
The invention discloses a preparation method of an oseltamivir phosphate compound, which is a method for continuously and automatically producing a compound and belongs to the field of organic chemistry. The preparation method comprises the processes of solution preparation, reaction, mixing, centrifugation, stirring, heating, decoloration, cooling, centrifugation, drying and the like. And (3) conveying the reactants by using a metering diaphragm pump, adjusting the yield of the product by adjusting the conveying speed, and finally, centrifugally drying to obtain the target product. The preparation method greatly shortens the production period, reduces the manual use, improves the safety in the production process and reduces the use of materials.
Description
Technical Field
The invention belongs to the field of organic chemistry, and particularly relates to a continuous oseltamivir phosphate compound and a preparation method thereof.
Background
Influenza is an acute respiratory infection caused by RNA (Ribonucleic Acid) viruses. It is transmitted in a variety of ways, such as airborne transmission, person-to-person contact transmission or transmission in contact with contaminated objects, etc., with extremely high mortality rates among critically ill patients. And the influenza virus has extremely high mutation rate and strong infectivity, and the gene is easy to be recombined and mutated, so that once influenza outbreak occurs, huge personal death and property loss can be caused. It is understood that 10% -20% of the us are affected annually, at least over ten thousand people are lost annually, and economic losses of up to billions of dollars are incurred.
After the influenza virus is propagated in host cells and spreads out of the cells in a budding mode, neuraminidase is used for catalyzing sialic acid hydrolysis to release the connection between the host cells and mature virus particles, and other healthy host cells are invaded. Therefore, the formation of virus particles can be prevented by inhibiting the activity of neuraminidase, and the spread of the virus can be prevented. The neuraminic acid inhibitor of the anti-influenza drug which is currently considered to be the most effective, the safest and the most specific is oseltamivir phosphate. There are many methods for synthesizing oseltamivir phosphate, and the oseltamivir phosphate can be directly synthesized through chemical reaction or synthesized after an oseltamivir phosphate intermediate is synthesized.
The CN109438276A patent discloses a synthesis method of oseltamivir phosphate. The method comprises the specific steps of removing tert-butyl from a compound 2 in trifluoroacetic acid at 40-60 ℃ through an azide-free reaction to obtain a compound 3, removing diallyl from alcohol at 60-78 ℃ from the compound 3, and then forming a salt with phosphoric acid, wherein diethanolamine or ammonium formate is used as a hydrogen donor, 10% palladium carbon is used as a catalyst to obtain an oseltamivir phosphate crude product, and then the oseltamivir phosphate crude product is refined by using an ethanol water solution to obtain the oseltamivir phosphate of the crystal form A. The method has the advantages of various raw materials, more complicated specific operation steps and longer preparation period.
The CN108484467A patent discloses a preparation method of oseltamivir phosphate. Reacting the Intermediate (IV) in the solvent with palladium acetate, triphenylphosphine and N, N-dimethyl barbituric acid, removing allyl at the reaction temperature of 20-25 ℃ to obtain an intermediate shown in a formula (III), and then carrying out acid treatment at the reaction temperature of 35-50 ℃. Removing tert-butyl to obtain oseltamivir free base, finally reacting with phosphoric acid in a solvent, and crystallizing and purifying, wherein the reaction temperature is 45-50 ℃. The method adopts nitrogen protection, has huge consumption, harsh experimental safety conditions and lower yield, and is not suitable for large-scale industrial production.
The CN101801914B patent discloses a method for producing oseltamivir phosphate from shikimic acid. The step is that shikimic acid is firstly treated with R2Esterification of OH to form a compound of formula III at a temperature of 70-100 deg.C, followed by reaction with methanesulfonyl chloride to form a trimethanesulfonate ester at a temperature of 0-5 deg.C, followed by regioselective S via an azidation agentNThe 3-methanesulfonate group of the 2-substituted trimethanesulfonate IV forms an azide, which is reduced with a trialkyl phosphite to form an aziridine, the temperature is controlled at 0-25 ℃ and the aziridine is opened to form the compound phosphoramide which is then converted to the compound of formula IX which is reduced to form the final target product of formula IX. The method has the advantages of long preparation period, complex preparation steps, high experimental safety requirement due to the use of strong acid, strong alkali and other solutions in the laboratory process, and is not suitable for large-scale industrial production.
In order to improve the synthesis yield of oseltamivir phosphate, researchers have conducted a lot of research, but the existing preparation methods at home and abroad still have the problems of low yield, high cost, long production period, use of toxic and explosive products in the preparation process, substandard heavy metal of the product and the like, and cannot meet the demand of people on the yield of oseltamivir, so that the preparation method with low production cost, high yield and yield is urgently needed.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a continuous synthesis method of oseltamivir phosphate, which can effectively improve the yield of oseltamivir phosphate production, greatly reduce the preparation period and meet the requirement of high-quality oseltamivir phosphate, and meanwhile, the preparation method has low cost and simple process and is suitable for large-scale industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
a method for continuously synthesizing oseltamivir phosphate comprises the following steps:
(1) preparing a solution: respectively preparing a solution A and a solution B;
the solution A consists of an intermediate 11, absolute ethyl alcohol and triphenyl phosphine;
the solution B consists of 1, 3-dimethyl barbituric acid, absolute ethyl alcohol and triphenyl phosphine;
adding the solution A and the solution B into a mixing module at the same time, and mixing to obtain a mixture C;
(2) reaction: transferring the mixture C obtained in the step (1) to a reaction module for reaction to obtain a reactant D;
(3) mixing: transferring the phosphoric acid ethanol solution and the reactant D obtained in the step (2) to a cooling module 1 together for cooling to obtain a reactant E;
(4) centrifuging: transferring the reactant E obtained in the step (3) to a centrifugal module for centrifugation, discarding supernatant, and collecting solid materials;
(5) stirring: transferring the solid material obtained in the step (4) to a stirring module, and simultaneously adding acetone to stir and mix to obtain a reactant F;
(6) heating: transferring the reactant F obtained in the step (5) to a heating module for heating to obtain a reactant G;
(7) and (3) decoloring: transferring the reactant G obtained in the step (6) to a decoloring module for decoloring to obtain a reactant H;
(8) cooling: transferring the reactant H obtained in the step (7) to a cooling module 2 for cooling to obtain a reactant I;
(9) centrifugal drying: and (4) transferring the reactant I obtained in the step (8) to a centrifugal drying module for centrifugation and drying, and obtaining a solid which is oseltamivir phosphate.
Further, the solution A described in the step (1) is an 35.52% by weight anhydrous ethanol solution of the intermediate 11, wherein the chemical name of the intermediate 11 (3R,4R,5S) -ethyl4-acetamido-5- (dialylamino) -3- (pentan-3-yloxy) cyclohex-1-enecarboxanoate, and 100.0 g of triphenylphosphine is added to the solution A per 1500.00Kg of anhydrous ethanol.
In the present invention, the intermediate 11 has the structural formula:
further, the solution B in the step (1) is 14.14 percent by weight of 1, 3-dimethyl barbituric acid in absolute ethanol, and 100.0 g of triphenyl phosphine is added in every 1500.00Kg of absolute ethanol used in the solution B.
Further, the mixing module in step (1) includes, but is not limited to, using a mixer.
Further, the adding speed of the solution A and the solution B in the step (1) is 0.99L/min-1.01L/min; the apparatus used for addition includes, but is not limited to, a metering diaphragm pump.
Further, the reaction module described in step (2) includes, but is not limited to, the use of a reactor.
Further, in the step (2), the temperature of the reaction module is controlled to be 75-80 ℃ all the time, and preferably, the temperature of the reaction module is 78 ℃.
Further, a reticular high-performance 10% Pd carbon carrier is loaded in the reaction module in the step (2).
Further, the weight percentage of the phosphoric acid ethanol solution in the step (3) is 15.65%, the adding speed is 0.32L/min-0.34L/min, and the adding equipment comprises but is not limited to a metering diaphragm pump.
Further, the cooling module 1 in step (3) includes, but is not limited to, using a mixer.
Further, the temperature of the cooling module 1 in the step (3) is 5-10 ℃, and preferably, the temperature of the cooling module 1 is 8 ℃.
Further, the centrifugation module in step (4) includes, but is not limited to, using a bottom-discharge centrifuge, and the centrifugation rate is 1000 rpm.
Further, the stirring module in step (5) includes, but is not limited to, using a mixer, and the stirring rate is 45 rpm.
Further, the adding speed of the acetone in the step (5) is 0.66L/min-0.68L/min; the apparatus used for addition includes, but is not limited to, a metering diaphragm pump.
Further, the heating module described in step (6) includes, but is not limited to, the use of a mixer.
Further, the heating temperature in the step (6) is 50-60 ℃, preferably, the heating temperature is 55 ℃.
Further, the decolorizing module described in step (7) includes, but is not limited to, an activated carbon decolorizer.
Further, the decolorization in the step (7) is activated carbon rod decolorization.
Further, the decoloring temperature in the step (7) is 50 to 60 ℃, preferably, the decoloring temperature is 55 ℃.
Further, the cooling module 2 in step (8) includes, but is not limited to, using a mixer.
Further, the temperature of the cooling module 2 in the step (8) is 0-5 ℃, and preferably, the temperature of the cooling module 2 is 3 ℃.
Further, the centrifugal drying module in the step (9) includes, but is not limited to, using a centrifuge, wherein the centrifugation rate is 1000 rpm, the centrifugation temperature is 0-5 ℃, and the drying temperature is controlled at 40-45 ℃; preferably, the centrifugation temperature is 3 ℃ and the drying temperature is 42 ℃.
Compared with the prior art, the beneficial effects of the invention are that (compared with the traditional process and the process applied by the invention, the traditional process is 5 batches calculated according to the same yield of 1.0 ton of oseltamivir API):
(1) in terms of production cycle, a single batch of 5 days by 5 batches to 25 days in the conventional process, a single batch of 1500kg of absolute ethanol at the beginning of the process of the invention uses 7500kg of absolute ethanol, and about 9375L of absolute ethanol, the sample amount per hour is 60L (1.0L/min), the total time is 156.25 hours, and the conversion is 6.5 days. The production time is greatly reduced.
(2) In the aspect of manual use, the traditional process needs post setting operation for safety, the unit operation mode of the traditional process flow chart needs 5-6 workers to complete the operation, and in the process disclosed by the invention, the modular operation is adopted, the occupied area of the modules is small, the comprehensive automation is realized, and 2-3 workers are required.
(3) Considering from the aspect of safety, in the traditional process, process pipelines are complex, the occupied area and the space area are large, the process pipelines are difficult to comprehensively look at in place, the potential safety hazards are many, and accidents are easy to happen; even part of the materials can contact air in the process of transferring and using, and nodes with unorganized emission are increased. The conventional kettle is 3000L, the liquid nitrogen is used for integrally cooling the main reaction kettle, the volume at normal temperature is large, and accidents are easy to happen. The traditional process needs to continue to react for 10 hours under the high-temperature condition, the volume of a reaction system is large, and certain potential safety hazards are also caused. In the process, the pipeline is simple, all materials are quantitatively conveyed in a metering mode, and the occupied area is small due to computer control; the possibility of exposing the materials in the air is extremely low, and the unorganized discharge is not easy to cause. The high-temperature area only has a small part of the reaction module, and the front part and the rear part can be cut off, so that the loss caused by accidents is small.
(4) In the aspect of medicine safety and sanitation (GMP), the steps of the traditional process are required to be carried out in a GMP workshop, the pipelines and the pipelines are relatively complex, the control in a GMP quality system is relatively difficult, the control conditions for the workshop are relatively high, and the facility investment is relatively large. The process of the invention is a standard executed in current GMP workshops for realizing full-automatic production and continuous production, and reduces the exposure of materials and the control of human factors as much as possible.
(5) From the aspect of material selection, in the traditional process, the activated carbon cannot be recycled and mixed in a reaction system, and cannot be used after the filtration is finished. The unusable active carbon can only become solid waste. 250.0kg of active carbon is needed for producing 1 ton of the catalyst, 1250.0kg of active carbon is needed for producing 5 ton of the catalyst, the adsorption product amount of the active carbon is 2 percent, palladium acetate is used in the traditional process, and the palladium acetate is dissolved in reaction liquid (Pd)-Free state) and is difficult to control the heavy metal Pd of the product (Pd is less than or equal to 10ppm detection amount specified by the national formulary). The process of the invention selects the high-performance activated carbon filter rod, not only can effectively remove color and has a long period, but also 50.0kg of the filter rod is used for producing 5 tons of oseltamivir API. The less activated carbon used, the higher the yield. Book (I)The process of the invention selects the high-performance catalyst of 10 percent Pd carbon, can be repeatedly used, and Pd is loaded on the carbon in a monomer form without free Pd-Appear and cannot enter a product system. A significant cost savings is realized in the replacement of this material.
Detailed Description
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
The raw materials adopted in the embodiment of the invention are all common implementation products, and the source of the raw materials is not limited in the invention. Wherein, the process uses continuous and automatic production.
The raw material sources are as follows:
the intermediate 11 is purchased from Spanish Huafeng New Material Co., Ltd, and has a product number of HF 401-R11;
the Pd carbon carrier is purchased from New Material Co., Ltd of Xian Kai, and the product number is 10% high-efficiency catalyst;
the activated carbon rod is purchased from environmental protection science and technology GmbH of Jiangsu Prishida, and the product number is coconut shell type activated carbon;
anhydrous ethanol is purchased from chemical engineering Co., Ltd, Shanxi Mobei Biotech Co., Ltd, 1, 3-dimethyl barbituric acid is purchased from Shanghai Heteropotential chemical engineering Co., Ltd (networked mall), phosphoric acid is purchased from Shanxi Mobei Biotech Co., Ltd, ethanol is purchased from Shanxi Mobei Biotech Co., Ltd, and acetone is purchased from Shaxi Mobei Biotech Co., Ltd.
Example 1
A method for continuously synthesizing oseltamivir phosphate comprises the following steps:
(1) preparing a solution: respectively preparing a solution A and a solution B;
solution A comprises 1074.00kg of intermediate 11, 3023.65kg of absolute ethyl alcohol and 0.20kg of anhydrous ethyl alcohol solution of intermediate 11 with the weight percentage of 35.52 percent, wherein the weight percentage of the absolute ethyl alcohol solution of intermediate 11 is 0.20kg of triphenyl phosphine;
the solution B is 14.14 percent of 1.3-dimethyl barbituric acid absolute ethanol solution consisting of 427.54kg of 1.3-dimethyl barbituric acid, 3023.65kg of absolute ethanol and 0.20kg of triphenylphosphine in percentage by weight;
adding the solution A and the solution B into a mixing module at the same time, mixing to obtain a mixture C; wherein the solution is
Conveying the solution A and the solution B by using a metering diaphragm pump at the conveying flow rate of 0.99L/min;
(2) reaction: transferring the mixture C to a reaction module, loading a reticular high-performance 10% Pd carbon carrier in the reaction module, and controlling the temperature of the reaction module at 78 ℃ all the time to obtain a reactant D after reaction;
(3) mixing: 2028.75kg of phosphoric acid ethanol solution (wherein the weight percentage of the phosphoric acid ethanol solution is 15.65%) and the reactant D are jointly transferred to a cooling module 1 for cooling, and the temperature of the cooling module 1 is 8 ℃ to obtain a reactant E; wherein the adding speed is 0.32L/min, and the used adding instrument is a metering diaphragm pump;
(4) centrifuging: transferring the reactant E to a centrifugal module for centrifugation at the centrifugal rate of 1000 revolutions per minute, discarding the supernatant, and collecting the solid material;
(5) stirring: transferring the solid material to a stirring module, and simultaneously adding 4051.69kg of acetone for stirring and mixing, wherein the acetone is conveyed by a metering diaphragm pump, the conveying speed is 0.66L/min, and the stirring speed is 45 revolutions per minute, so as to obtain a reactant F;
(6) heating: transferring the reactant F to a heating module, wherein the heating temperature is 55 ℃, and heating to obtain a reactant G;
(7) and (3) decoloring: transferring the reactant G to a decoloring module to perform activated carbon rod decoloring at the decoloring temperature of 55 ℃ to obtain a reactant H;
(8) cooling: transferring the reactant H to a cooling module 2, wherein the temperature of the cooling module 2 is 3 ℃, and cooling to obtain a reactant I;
(9) centrifugal drying: transferring the reactant I to a centrifugal drying module for centrifugation and drying, wherein the centrifugation temperature is 3 ℃, the drying temperature is 42 ℃, and the obtained solid is oseltamivir phosphate.
Example 2
A method for continuously synthesizing oseltamivir phosphate comprises the following steps:
(1) preparing a solution: respectively preparing a solution A and a solution B;
solution A comprises 1074.00kg of intermediate 11, 3023.65kg of absolute ethyl alcohol and 0.20kg of anhydrous ethyl alcohol solution of intermediate 11 with the weight percentage of 35.52 percent, wherein the weight percentage of the absolute ethyl alcohol solution of intermediate 11 is 0.20kg of triphenyl phosphine;
the solution B is 14.14 percent of 1.3-dimethyl barbituric acid absolute ethanol solution consisting of 427.54kg of 1.3-dimethyl barbituric acid, 3023.65kg of absolute ethanol and 0.20kg of triphenylphosphine in percentage by weight;
adding the solution A and the solution B into a mixing module at the same time, mixing to obtain a mixture C; wherein the solution is
Conveying the solution A and the solution B by using a metering diaphragm pump at the conveying flow rate of 1.00L/min;
(2) reaction: transferring the mixture C to a reaction module, loading a reticular high-performance 10% Pd carbon carrier in the reaction module, and controlling the temperature of the reaction module at 78 ℃ all the time to obtain a reactant D after reaction;
(3) mixing: 2028.75kg of phosphoric acid ethanol solution (wherein the weight percentage of the phosphoric acid ethanol solution is 15.65%) and the reactant D are jointly transferred to a cooling module 1 for cooling, and the temperature of the cooling module 1 is 8 ℃ to obtain a reactant E; wherein the adding speed is 0.33L/min, and the used adding instrument is a metering diaphragm pump;
(4) centrifuging: transferring the reactant E to a centrifugal module for centrifugation at the centrifugal rate of 1000 revolutions per minute, discarding the supernatant, and collecting the solid material;
(5) stirring: transferring the solid material to a stirring module, and simultaneously adding 4051.69kg of acetone for stirring and mixing, wherein the acetone is conveyed by a metering diaphragm pump, the conveying speed is 0.67L/min, and the stirring speed is 45 revolutions per minute, so as to obtain a reactant F;
(6) heating: transferring the reactant F to a heating module, wherein the heating temperature is 55 ℃, and heating to obtain a reactant G; (7) and (3) decoloring: transferring the reactant G to a decoloring module to perform activated carbon rod decoloring at the decoloring temperature of 55 ℃ to obtain a reactant H;
(8) cooling: transferring the reactant H to a cooling module 2, wherein the temperature of the cooling module 2 is 3 ℃, and cooling to obtain a reactant I;
(9) centrifugal drying: transferring the reactant I to a centrifugal drying module for centrifugation and drying, wherein the centrifugation temperature is 3 ℃, the drying temperature is 42 ℃, and the obtained solid is oseltamivir phosphate.
Example 3
A method for continuously synthesizing oseltamivir phosphate comprises the following steps:
(1) preparing a solution: respectively preparing a solution A and a solution B;
solution A comprises 1074.00kg of intermediate 11, 3023.65kg of absolute ethyl alcohol and 0.20kg of anhydrous ethyl alcohol solution of intermediate 11 with the weight percentage of 35.52 percent, wherein the weight percentage of the absolute ethyl alcohol solution of intermediate 11 is 0.20kg of triphenyl phosphine;
the solution B is 14.14 percent of 1.3-dimethyl barbituric acid absolute ethanol solution consisting of 427.54kg of 1.3-dimethyl barbituric acid, 3023.65kg of absolute ethanol and 0.20kg of triphenylphosphine in percentage by weight;
adding the solution A and the solution B into a mixing module at the same time, mixing to obtain a mixture C; wherein the solution is
Conveying the solution A and the solution B by using a metering diaphragm pump at the conveying flow rate of 1.01L/min;
(2) reaction: transferring the mixture C to a reaction module, loading a reticular high-performance 10% Pd carbon carrier in the reaction module, controlling the temperature of the reaction module at 80 ℃ all the time, and reacting to obtain a reactant D;
(3) mixing: 2028.75kg of phosphoric acid ethanol solution (wherein the weight percentage of the phosphoric acid ethanol solution is 15.65%) and the reactant D are jointly transferred to a cooling module 1 for cooling, and the temperature of the cooling module 1 is 10 ℃ to obtain a reactant E; wherein the adding speed is 0.34L/min, and the used adding instrument is a metering diaphragm pump;
(4) centrifuging: transferring the reactant E to a centrifugal module for centrifugation at the centrifugal rate of 1000 revolutions per minute, discarding the supernatant, and collecting the solid material;
(5) stirring: transferring the solid material to a stirring module, and simultaneously adding 4051.69kg of acetone for stirring and mixing, wherein the acetone is conveyed by a metering diaphragm pump, the conveying speed is 0.68L/min, and the stirring speed is 45 revolutions per minute, so as to obtain a reactant F;
(6) heating: transferring the reactant F to a heating module, wherein the heating temperature is 60 ℃, and heating to obtain a reactant G;
(7) and (3) decoloring: transferring the reactant G to a decoloring module to perform activated carbon rod decoloring at the decoloring temperature of 60 ℃ to obtain a reactant H;
(8) cooling: transferring the reactant H to a cooling module 2, wherein the temperature of the cooling module 2 is 5 ℃, and cooling to obtain a reactant I;
(9) centrifugal drying: transferring the reactant I to a centrifugal drying module for centrifugation and drying, wherein the centrifugation temperature is 5 ℃, the drying temperature is 45 ℃, and the obtained solid is oseltamivir phosphate.
Example 4
A method for continuously synthesizing oseltamivir phosphate comprises the following steps:
(1) preparing a solution: respectively preparing a solution A and a solution B;
solution A comprises 1074.00kg of intermediate 11, 3023.65kg of absolute ethyl alcohol and 0.20kg of anhydrous ethyl alcohol solution of intermediate 11 with the weight percentage of 35.52 percent, wherein the weight percentage of the absolute ethyl alcohol solution of intermediate 11 is 0.20kg of triphenyl phosphine;
the solution B is 14.14 percent of 1.3-dimethyl barbituric acid absolute ethanol solution consisting of 427.54kg of 1.3-dimethyl barbituric acid, 3023.65kg of absolute ethanol and 0.20kg of triphenylphosphine in percentage by weight;
adding the solution A and the solution B into a mixing module at the same time, mixing to obtain a mixture C; wherein the solution is
Conveying the solution A and the solution B by using a metering diaphragm pump at the conveying flow rate of 1.00L/min;
(2) reaction: transferring the mixture C to a reaction module, loading a reticular high-performance 10% Pd carbon carrier in the reaction module, controlling the temperature of the reaction module at 75 ℃ all the time, and reacting to obtain a reactant D;
(3) mixing: 2028.75kg of phosphoric acid ethanol solution (wherein the weight percentage of the phosphoric acid ethanol solution is 15.65%) and the reactant D are jointly transferred to a cooling module 1 for cooling, and the temperature of the cooling module 1 is 5 ℃ to obtain a reactant E; wherein the adding speed is 0.33L/min, and the used adding instrument is a metering diaphragm pump;
(4) centrifuging: transferring the reactant E to a centrifugal module for centrifugation at the centrifugal rate of 1000 revolutions per minute, discarding the supernatant, and collecting the solid material;
(5) stirring: transferring the solid material to a stirring module, and simultaneously adding 4051.69kg of acetone for stirring and mixing, wherein the acetone is conveyed by a metering diaphragm pump, the conveying speed is 0.66L/min, and the stirring speed is 45 revolutions per minute, so as to obtain a reactant F;
(6) heating: transferring the reactant F to a heating module, wherein the heating temperature is 50 ℃, and heating to obtain a reactant G;
(7) and (3) decoloring: transferring the reactant G to a decoloring module to perform activated carbon rod decoloring at the decoloring temperature of 50 ℃ to obtain a reactant H;
(8) cooling: transferring the reactant H to a cooling module 2, wherein the temperature of the cooling module 2 is 0 ℃, and cooling to obtain a reactant I;
(9) centrifugal drying: transferring the reactant I to a centrifugal drying module for centrifugation and drying, wherein the centrifugation temperature is 0 ℃, the drying temperature is 40 ℃, and the obtained solid is oseltamivir phosphate.
Example 5
A method for continuously synthesizing oseltamivir phosphate comprises the following steps:
(1) preparing a solution: respectively preparing a solution A and a solution B;
solution A is composed of 1074.00kg of intermediate 11, 3023.65kg of absolute ethyl alcohol and 0.20kg of triphenyl phosphine, and is 35.52 percent of absolute ethyl alcohol solution of intermediate 11 by weight percent;
the solution B is 14.14 percent of 1.3-dimethyl barbituric acid absolute ethanol solution consisting of 427.54kg of 1.3-dimethyl barbituric acid, 3023.65kg of absolute ethanol and 0.20kg of triphenylphosphine in percentage by weight;
adding the solution A and the solution B into a mixing module at the same time, mixing to obtain a mixture C; wherein the solution is
Conveying the solution A and the solution B by using a metering diaphragm pump at the conveying flow rate of 1.00L/min;
(2) reaction: transferring the mixture C to a reaction module, loading a reticular high-performance 10% Pd carbon carrier in the reaction module, and controlling the temperature of the reaction module at 78 ℃ all the time to obtain a reactant D after reaction;
(3) mixing: 2028.75kg of phosphoric acid ethanol solution (wherein the weight percentage of the phosphoric acid ethanol solution is 15.65%) and the reactant D are jointly transferred to a cooling module 1 for cooling, and the temperature of the cooling module 1 is 8 ℃ to obtain a reactant E; wherein the adding speed is 0.33L/min, and the used adding instrument is a metering diaphragm pump;
(4) centrifuging: transferring the reactant E to a centrifugal module for centrifugation at the centrifugal rate of 1000 revolutions per minute, discarding the supernatant, and collecting the solid material;
(5) stirring: transferring the solid material to a stirring module, and simultaneously adding 4051.69kg of acetone for stirring and mixing, wherein the acetone is conveyed by a metering diaphragm pump, the conveying speed is 0.68L/min, and the stirring speed is 45 revolutions per minute, so as to obtain a reactant F;
(6) heating: transferring the reactant F to a heating module, wherein the heating temperature is 55 ℃, and heating to obtain a reactant G;
(7) and (3) decoloring: transferring the reactant G to a decoloring module to perform activated carbon rod decoloring at the decoloring temperature of 55 ℃ to obtain a reactant H;
(8) cooling: transferring the reactant H to a cooling module 2, wherein the temperature of the cooling module 2 is 3 ℃, and cooling to obtain a reactant I;
(9) centrifugal drying: transferring the reactant I to a centrifugal drying module for centrifugation and drying, wherein the centrifugation temperature is 3 ℃, the drying temperature is 42 ℃, and the obtained solid is oseltamivir phosphate.
Comparative example 1
The difference from example 2 is that, in step (1):
solution A is composed of 1074.00kg of intermediate 11, 3580.00kg of absolute ethyl alcohol and 0.20kg of triphenyl phosphine, and is a 30 percent absolute ethyl alcohol solution of intermediate 11 by weight percent;
other raw material ratios and preparation methods were the same as in example 2.
Comparative example 2
The difference from example 2 is that, in step (1):
solution A consists of 635.81kg of intermediate 11, 3580.00kg of absolute ethyl alcohol and 0.20kg of triphenyl phosphine, and is a 17.76 percent absolute ethyl alcohol solution of intermediate 11 by weight percent;
the solution B is an absolute ethanol solution of 7.07 percent by weight of 1, 3-dimethyl barbituric acid, which consists of 213.77kg of 1, 3-dimethyl barbituric acid, 3023.65kg of absolute ethanol and 0.20kg of triphenyl phosphine;
other raw material ratios and preparation methods were the same as in example 2.
Comparative example 3
The difference from example 2 is that, in step (1):
the solution B is 10 percent of 1, 3-dimethyl barbituric acid absolute ethanol solution consisting of 427.54kg of 1, 3-dimethyl barbituric acid, 4275.54kg of absolute ethanol and 0.20kg of triphenylphosphine in percentage by weight;
other raw material ratios and preparation methods were the same as in example 2.
Comparative example 4
The difference from example 2 is that 2028.75kg of phosphoric acid ethanol solution (wherein the weight percentage of the phosphoric acid ethanol solution is 18%) is added in the step (3);
other raw material ratios and preparation methods were the same as in example 2.
Comparative example 5
The difference from the example 2 is that 2028.75kg of phosphoric acid ethanol solution (wherein the weight percentage of the phosphoric acid ethanol solution is 12%) is added in the step (3);
other raw material ratios and preparation methods were the same as in example 2.
Comparative example 6
The difference from example 2 is that the temperature of the reaction module in step (2) is 70 ℃;
other raw material ratios and preparation methods were the same as in example 2.
Comparative example 7
The difference from example 2 is that the temperature of the reaction module in step (2) is 85 ℃;
other raw material ratios and preparation methods were the same as in example 2.
Comparative example 8
The difference from example 2 is that the temperature of the decoloring module in step (2) is 45 ℃;
other raw material ratios and preparation methods were the same as in example 2.
Comparative example 9
The difference from example 2 is that the temperature of the decoloring module in step (2) is 65 ℃;
other raw material ratios and preparation methods were the same as in example 2.
Comparative example 10
The oseltamivir phosphate is prepared by the original process.
The original process is summarized as follows: 1500.00kg of absolute ethyl alcohol is added into a 3000L reaction kettle, the kettle cover is opened, 105.99kg of 1.3-dimethyl barbituric acid, 0.10kg of triphenylphosphine, 2.66kg of palladium acetate and 266.42kg of oseltamivir important intermediate 11 are added, nitrogen is replaced for 3 times, and then the reaction kettle is stirred and mixed evenly. Heating the reaction kettle to 75-80 ℃ and reacting for 10 hours. The complete conversion of intermediate 11 to intermediate 12 was monitored by HPLC. And (3) reducing the temperature in the kettle to normal temperature, filtering by using a bag filter A to remove mechanical impurities, and filtering the reaction liquid to a crystallization kettle. 78.25kg of phosphoric acid and 500.00kg of absolute ethyl alcohol are added into the crystallization kettle, and the temperature is controlled between 5 ℃ and 10 ℃ to be stirred for 3 hours. Centrifuging by a centrifuge A, and putting the centrifuged solid into a decoloring kettle. And opening 1000.00kg of acetone into the decoloring kettle, opening a cover, adding 50.00kg of activated carbon, heating to 50-60 ℃, stirring for 2 hours, quickly filtering by using a bag filter B to a crystallization kettle to remove the activated carbon, and stirring for 3 hours while controlling the temperature of the crystallization kettle to be 5-10 ℃. Centrifuge through centrifuge a. And (3) centrifuging to obtain a solid, conveying the solid into a positive air drying box, and continuously drying the solid for 10 hours at the drying temperature of 35-45 ℃ in a vacuum drier to obtain 200.56g of oseltamivir phosphate.
The experimental results obtained in examples 1 to 5 and comparative examples 1 to 10 were analyzed, and the results are shown in table 1.
TABLE 1
Claims (10)
1. A continuous synthesis method of oseltamivir phosphate is characterized by comprising the following steps:
(1) preparing a solution: respectively preparing a solution A and a solution B;
the solution A consists of an intermediate 11, absolute ethyl alcohol and triphenyl phosphine;
the solution B consists of 1, 3-dimethyl barbituric acid, absolute ethyl alcohol and triphenyl phosphine;
adding the solution A and the solution B into a mixing module at the same time, and mixing to obtain a mixture C;
(2) reaction: transferring the mixture C obtained in the step (1) to a reaction module for reaction to obtain a reactant D;
(3) mixing: transferring the phosphoric acid ethanol solution and the reactant D obtained in the step (2) to a cooling module 1 together for cooling to obtain a reactant E;
(4) centrifuging: transferring the reactant E obtained in the step (3) to a centrifugal module for centrifugation, discarding supernatant, and collecting solid materials;
(5) stirring: transferring the solid material obtained in the step (4) to a stirring module, and simultaneously adding acetone to stir and mix to obtain a reactant F;
(6) heating: transferring the reactant F obtained in the step (5) to a heating module for heating to obtain a reactant G;
(7) and (3) decoloring: transferring the reactant G obtained in the step (6) to a decoloring module for decoloring to obtain a reactant H;
(8) cooling: transferring the reactant H obtained in the step (7) to a cooling module 2 for cooling to obtain a reactant I;
(9) centrifugal drying: and (4) transferring the reactant I obtained in the step (8) to a centrifugal drying module for centrifugation and drying, and obtaining a solid which is oseltamivir phosphate.
2. The method according to claim 1, wherein the solution A in step (1) is 35.52% by weight of the intermediate 11 in absolute ethanol, wherein the chemical name of the intermediate 11 (3R,4R,5S) -ethyl4-acetamido-5- (dialylamino) -3- (pentan-3-yloxy) cyclohexex-1-enecarboxlate is added to 100.0 g of triphenylphosphine per 1500.00Kg of absolute ethanol; the solution B is 14.14 percent of absolute ethanol solution of 1, 3-dimethyl barbituric acid, and 100.0 g of triphenyl phosphine is added into 1500.00Kg of absolute ethanol in the solution B; the adding speed of the solution A and the solution B is 0.99L/min-1.01L/min.
3. The preparation method according to claim 1, wherein the reaction module in step (2) is loaded with a reticular high-performance 10% Pd carbon carrier, and the temperature of the reaction module is controlled to be 75-80 ℃ all the time.
4. The method according to claim 1, wherein the weight percentage of the phosphoric acid ethanol solution in the step (3) is 15.65%, and the adding speed is 0.32L/min-0.34L/min; the temperature of the cooling module 1 is 5-10 ℃.
5. The method of claim 1, wherein the centrifugation in step (4) is performed at a rate of 1000 rpm.
6. The method according to claim 1, wherein the stirring in the step (5) is carried out at a rate of 45 rpm; the addition rate of acetone is 0.66L/min-0.68L/min.
7. The method according to claim 1, wherein the temperature of the heating in the step (6) is 50 to 60 ℃.
8. The method according to claim 1, wherein the decolorization in the step (7) is activated carbon rod decolorization, and the temperature of the decolorization is 50 to 60 ℃.
9. The method according to claim 1, wherein the temperature of the cooling module 2 in the step (8) is 0-5 ℃.
10. The method according to claim 1, wherein the centrifugation rate in the step (9) is 1000 rpm, the centrifugation temperature is 0 to 5 ℃, and the drying temperature is 40 to 45 ℃.
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| CN101343241A (en) * | 2007-07-10 | 2009-01-14 | 上海三维制药有限公司 | Purification process for Oseltamivir Phosphate |
| CN109438276A (en) * | 2018-09-04 | 2019-03-08 | 西安吉泰医药有限公司 | A kind of preparation method of Oseltamivir phosphate |
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| CN101343241A (en) * | 2007-07-10 | 2009-01-14 | 上海三维制药有限公司 | Purification process for Oseltamivir Phosphate |
| CN109438276A (en) * | 2018-09-04 | 2019-03-08 | 西安吉泰医药有限公司 | A kind of preparation method of Oseltamivir phosphate |
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