CN112250601B - Method for safely and nontoxic removing nickel ion impurities in peramivir trihydrate intermediate M9 - Google Patents
Method for safely and nontoxic removing nickel ion impurities in peramivir trihydrate intermediate M9 Download PDFInfo
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Abstract
The invention provides a method for safely and nontoxic removal of nickel ion impurities in a peramivir trihydrate intermediate M9, which comprises the following steps: adding pure water into a reaction kettle containing the crude peramivir trihydrate, wherein the temperature is-5 ℃; then dropwise adding an acidic solution to obtain a first solution after the dropwise adding is finished; adding pure water into the first solution again, heating to 15-20 ℃, preserving heat for 20-40 min, adding activated carbon, and stirring for 20-40 min to obtain a second solution; centrifuging the second solution to obtain a centrifugal filtrate and a first filter cake; leaching the first filter cake with purified water, and combining leached filtrate with centrifugal filtrate to obtain a third solution; and washing, crystallizing and the like the third solution to finally obtain the purified peramivir trihydrate. The method can effectively remove nickel ion impurities in the peramivir trihydrate, avoids using sodium nitrite in the process, avoids generating genotoxic impurities, and greatly improves the safety of the medicine.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a method for safely and non-toxic removing nickel ion impurities in a peramivir trihydrate intermediate M9.
Background
The synthesis routes of peramivir are reported less, and due to the structural particularity, the routes are also different in size, and are not different, but mainly reflected in the difference between individual intermediates and reaction reagents. Peramivir intermediate M8 is an important intermediate used in all routes, and the preparation of peramivir requires reduction of M8 to obtain M9 as an intermediate.
The difference lies in that the used reducing agent and the post-treatment are different, wherein, a sodium borohydride/nickel chloride reduction system has mild condition, does not need special equipment and is easy to operate, thereby being a main selection route in the synthesis process of the peramivir at present. Sodium nitrite is introduced in the post-treatment process, nitrite is used as a complexing agent of nickel ions, the method has the advantages of strong complexing ability and good solubility, and the nickel ions in a reaction system can be well removed without being reduced into metal chips or generating nickel boride by the system, but amino groups exist in the peramivir structure and react with nitroso groups to generate potential genotoxic impurities and N-nitroso compounds, and if the control is not good, potential risks are brought to the safety of medicaments.
Disclosure of Invention
The invention aims to solve the defects in the prior art and provides a safe method for removing nickel ion impurities in peramivir trihydrate without generating genotoxic impurities.
The technical scheme adopted by the invention is as follows: the method for safely and nontoxic removing nickel ion impurities in the peramivir trihydrate intermediate M9 comprises the following steps:
A. quenching: adding pure water into a reaction kettle containing the crude peramivir trihydrate, wherein the temperature is-5 ℃; then dropwise adding an acidic solution to obtain a first solution after the dropwise adding is finished; adding pure water into the first solution again, heating to 15-20 ℃, preserving heat for 20-40 min, adding activated carbon, and stirring for 20-40 min to obtain a second solution;
B. centrifugal leaching: carrying out centrifugal separation on the second solution to obtain centrifugal filtrate and a first filter cake, wherein the centrifugal filtrate is reserved; leaching the first filter cake with purified water, and combining leached filtrate with centrifugal filtrate to obtain a third solution;
C. adjusting the pH value: returning the third solution to the reaction kettle, cooling to-5 ℃, adjusting the pH to 11-12 by using ammonia water, and stirring while keeping the temperature; heating to 15-20 ℃, and preserving heat for 2-3 hours to obtain a fourth solution;
D. centrifugal washing: centrifuging the fourth solution until no liquid drops drip out, leaching the centrifuged solid phase with pure water to obtain a second filter cake, and repeatedly washing the second filter cake with ammonia water and an organic solvent to obtain an organic phase;
e: and (3) crystallization: and crystallizing the organic phase, and performing centrifugal separation, leaching and drying on the precipitated crystals to finally obtain the refined peramivir trihydrate.
Further, the specific steps of repeatedly washing the second filter cake in the step D are as follows: first, a first ammonia wash is performed: sequentially adding toluene, the second filter cake and ammonia water into a refining kettle, heating to 70-80 ℃, dissolving, stirring after dissolving, and refining and separating liquid to obtain a water phase and a first toluene phase; then, carrying out secondary ammonia water washing, adding ammonia water into the first toluene phase, heating to 70-80 ℃, dissolving, stirring after dissolving, and refining and separating liquid to obtain a water phase and a second toluene phase; finally, EDTA solution wash: adding an EDTA/water solution into the second xylene phase, heating to 70-80 ℃, dissolving and stirring; standing and separating to obtain an organic phase.
Further, the acidic solution in step a is one of citric acid, formic acid, acetic acid, propionic acid, malic acid, hydrochloric acid, sulfuric acid, phosphoric acid or carbonic acid.
Further, the molar ratio of the peramivir hydrate crude product to the acidic solution in the step A is 30: 0.05-45: 1.
And further, the time for dissolving and stirring in the step D is 0.2-0.6 h.
Further, the specific steps of step E are: slowly cooling the organic phase to 15-25 ℃, continuously stirring at 15-25 ℃, and centrifugally separating precipitated crystals; leaching the filter cake with toluene, centrifuging until no liquid drops drip out, and continuing centrifuging for 1 h; drying, and air-blast drying the filter cake at 40-50 ℃ for 4-6h to finally obtain the refined peramivir trihydrate PLMW-M9.
The beneficial effects obtained by the invention are as follows: the method can effectively remove nickel ion impurities in the peramivir trihydrate intermediate M9, avoids using sodium nitrite in the process, avoids generating genotoxic impurities, and greatly improves the safety of the medicament.
The principle of the invention is as follows: US20130274229 reports acid-soluble base-precipitation of M9 during the post-treatment; nickel or nickel boride is insoluble in acid solution, and therefore, the intermediate M9 and nickel metal are effectively separated without using sodium nitrite; complete complexation removal of small amounts of residual nickel ions using ammonia and EDTA was completely feasible to obtain standard peramivir intermediate M9.
Drawings
FIG. 1 is a HPLC chart of purity related substances of purified M9 of example 1 of the present invention;
FIG. 2 is an HPLC chart of M9 isomer-related substance purified in example 1 of the present invention;
FIG. 3 is a HPLC chart of purity related substances of purified M9 of example 2 of the present invention;
FIG. 4 is an HPLC chart of M9 isomer related substance purified according to example 2 of the present invention;
FIG. 5 is a HPLC chart of the substance related to purity of purified M9 by a conventional method.
FIG. 6 is a HPLC chart of M9 isomer related substance purified by a conventional method.
Detailed Description
The technical solutions in the embodiments of the present invention are clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.
In the specific implementation: the scheme for synthesis of peramivir M9 from peramivir M8 is as follows:
solution preparation:
preparing a sodium borohydride solution: the sodium borohydride solution is prepared in 6 batches, and the preparation method of each batch comprises the following steps: slowly adding 11.5g of sodium hydroxide into 5.36Kg of methanol for dissolving, slowly adding 0.62Kg of sodium borohydride, fully dissolving until no obvious particles are present, storing at room temperature for later use, and preparing for use;
preparing an EDTA solution: 2.1kg of EDTA-2Na salt and 28kg of purified water are uniformly mixed for later use, are insoluble at room temperature, are uniformly mixed during washing and are pumped into a reaction kettle;
preparing citric acid: adding 26.8Kg of purified water and 16.1Kg of citric acid into a 100L preparation vessel, slowly adding into water, stirring well, and cooling to room temperature for use.
Feeding: introducing nitrogen into a 200L reaction kettle for protection, adding 35Kg of methanol into the reaction kettle, starting stirring, sequentially adding 3.75Kg of starting materials PLMW-M814 Kg and nickel chloride hexahydrate into the reaction kettle, and stirring and dissolving.
Cooling: cooling to below-15 ℃, slowly dripping sodium borohydride solution, keeping the dripping temperature between-15 ℃ and-8 ℃, and changing the reaction liquid from light green to black suspension (the reaction is violent, gas is released, and the acceleration of suspended liquid drops of the sodium borohydride is strictly controlled); controlling the temperature to be-15 to-8 ℃, and stirring for 1 to 2 hours; obtaining crude PLMW-M9 containing nickel metal ion impurities.
The crude product of PLMW-M9 containing nickel metal ion impurities is taken as a sample, and the following steps are carried out to remove impurities.
Example 1:
a method for safely and nontoxic removing nickel ion impurities in peramivir trihydrate intermediate M9 comprises the following steps:
A. quenching: adding 35kg of pure water into a reaction kettle containing the crude peramivir trihydrate intermediate M9 at the temperature of-5 ℃; then 16.1kg of citric acid is added dropwise, and a first solution is obtained after the addition is finished; adding pure water into the first solution again, heating to 15-20 ℃, preserving heat for 20-40 min, adding activated carbon, and stirring for 20-40 min to obtain a second solution;
B. centrifugal leaching: carrying out centrifugal separation on the second solution to obtain centrifugal filtrate and a first filter cake, wherein the centrifugal filtrate is reserved; leaching the first filter cake with 14kg of purified water, and combining the leached filtrate with the centrifugal filtrate to obtain a third solution;
C. adjusting the pH value: returning the third solution to the reaction kettle, cooling to-5 ℃, adjusting the pH to 11-12 by using 49kg of ammonia water, and stirring while keeping the temperature; heating to 15-20 ℃, and preserving heat for 2-3 hours to obtain a fourth solution;
D. centrifugal washing: centrifuging the fourth solution until no liquid drops drip out, and leaching the centrifuged solid phase with pure water to obtain a second filter cake; first, a first ammonia wash is performed: sequentially adding 210kg of toluene, 29.4kg of second filter cake and 29.4kg of ammonia water into a refining kettle, heating to 70-80 ℃, dissolving, stirring for 0.5h after dissolving, refining and separating liquid to obtain a water phase and a first toluene phase; then, carrying out secondary ammonia water washing, adding 25.2kg of ammonia water into the first toluene phase, heating to 70-80 ℃, dissolving, stirring for 0.5h after dissolving, and refining and separating liquid to obtain a water phase and a second toluene phase; finally, EDTA solution wash: adding 30.1kg of EDTA/water solution into the xylene phase, heating to 70-80 ℃, dissolving and stirring for 0.5 h; standing for 10min for liquid separation, and separating out a water phase to obtain an organic phase;
e: and (3) crystallization: slowly cooling the organic phase to 15-25 ℃, continuously stirring for 3 hours at 15-25 ℃, and centrifugally separating precipitated crystals; leaching the filter cake with 25.2kg of toluene, centrifuging until no liquid drops drip out, and continuing to centrifuge for 1 h; drying, and drying the filter cake by blowing air at 40-50 ℃ for 4-6h to finally obtain the refined peramivir trihydrate PLMW-M9.
Example 2:
a method for safely and nontoxic removing nickel ion impurities in peramivir trihydrate comprises the following steps:
A. quenching: adding 35kg of pure water into a reaction kettle containing the peramivir trihydrate crude product at the temperature of-5 ℃; then, dropwise adding 15kg of citric acid, and obtaining a first solution after dropwise adding; adding pure water into the first solution again, heating to 15-20 ℃, preserving heat for 30min, adding activated carbon, and stirring for 30min to obtain a second solution;
B. centrifugal leaching: carrying out centrifugal separation on the second solution to obtain centrifugal filtrate and a first filter cake, wherein the centrifugal filtrate is reserved; leaching the first filter cake with 15kg of purified water, and combining the leached filtrate with the centrifuged filtrate to obtain a third solution;
C. adjusting the pH value: returning the third solution to the reaction kettle, cooling to-5 ℃, adjusting the pH to 11-12 by using 50kg of ammonia water, and stirring while keeping the temperature; heating to 15-20 ℃, and preserving heat for 2-3 hours to obtain a fourth solution;
D. centrifugal washing: centrifuging the fourth solution until no liquid drops drip out, and leaching the centrifuged solid phase with pure water to obtain a second filter cake; first, a first ammonia wash is performed: sequentially adding 200kg of toluene, the second filter cake and 32kg of ammonia water into a refining kettle, heating to 70-80 ℃, dissolving and clearing, stirring for 0.5h after dissolving and clearing, and refining and separating liquid to obtain a water phase and a first toluene phase; then, carrying out secondary ammonia water washing, adding 30kg of ammonia water into the first toluene phase, heating to 70-80 ℃, dissolving, stirring for 0.5h after dissolving, refining and separating liquid to obtain a water phase and a second toluene phase; finally, EDTA solution wash: adding 30.1kg of EDTA/water solution into the xylene phase, heating to 70-80 ℃, dissolving and stirring for 0.5 h; standing for 10min for liquid separation, and separating out a water phase to obtain an organic phase;
e: and (3) crystallization: slowly cooling the organic phase to 15-25 ℃, continuously stirring for 3 hours at 15-25 ℃, and centrifugally separating precipitated crystals; leaching the filter cake with 25.2kg of toluene, centrifuging until no liquid drops drop out, and continuing centrifuging for 1 h; drying, and air-blast drying the filter cake at 40-50 ℃ for 4-6h to finally obtain the refined peramivir trihydrate PLMW-M9.
The traditional method comprises the following steps: adopts sodium nitrite treatment.
Comparison of Experimental data results
Claims (4)
1. The method for safely and nontoxic removing nickel ion impurities in the peramivir trihydrate intermediate M9 is characterized by comprising the following steps: the method comprises the following steps:
A. quenching: adding pure water into a reaction kettle containing the crude peramivir trihydrate intermediate M9 at the temperature of-5 ℃; then dropwise adding an acidic solution to obtain a first solution after the dropwise adding is finished; adding pure water into the first solution again, heating to 15-20 ℃, preserving heat for 20-40 min, adding activated carbon, and stirring for 20-40 min to obtain a second solution;
B. centrifugal leaching: carrying out centrifugal separation on the second solution to obtain centrifugal filtrate and a first filter cake, wherein the centrifugal filtrate is reserved; leaching the first filter cake with purified water, and combining leached filtrate with centrifugal filtrate to obtain a third solution;
C. adjusting the pH value: returning the third solution to the reaction kettle, cooling to-5 ℃, adjusting the pH to 11-12 by using ammonia water, and stirring while keeping the temperature; heating to 15-20 ℃, and preserving heat for 2-3 hours to obtain a fourth solution;
D. centrifugal washing: centrifuging the fourth solution until no liquid drops drip out, leaching the centrifuged solid phase with pure water to obtain a second filter cake, and repeatedly washing the second filter cake with ammonia water and an organic solvent to obtain an organic phase;
e: and (3) crystallization: crystallizing the organic phase, and centrifugally separating, leaching and drying the separated crystal to finally obtain a refined peramivir trihydrate intermediate M9;
the chemical formula of peramivir trihydrate intermediate M9 is as follows:
the route for synthesizing the peramivir trihydrate intermediate M9 is as follows:
the step D of repeatedly washing the second filter cake comprises the following specific steps: first, a first ammonia wash is performed: sequentially adding toluene, the second filter cake and ammonia water into a refining kettle, heating to 70-80 ℃, dissolving and clearing, stirring for 0.2-0.6 h after dissolving and clearing, and refining and separating liquid to obtain a water phase and a first toluene phase; then, carrying out secondary ammonia water washing, adding ammonia water into the first toluene phase, heating to 70-80 ℃, dissolving, stirring for 0.2-0.6 h after dissolving, and refining and separating liquid to obtain a water phase and a second toluene phase; finally, EDTA solution wash: adding EDTA/water solution into the xylene phase, heating to 70-80 ℃, dissolving and clearing, and stirring for 0.2-0.6 h; standing and separating to obtain an organic phase.
2. The safe and nontoxic method for removing nickel ion impurities in peramivir trihydrate intermediate M9 according to claim 1, which is characterized in that: the molar ratio of the peramivir trihydrate intermediate M9 crude product to the acidic solution in the step A is 30: 0.05-45: 1.
3. The method for safely and non-toxic removing nickel ion impurities in peramivir trihydrate intermediate M9 according to claim 1 or 2, wherein the method comprises the following steps: the acid solution in the step A is one of citric acid, formic acid, acetic acid, propionic acid, malic acid, hydrochloric acid, sulfuric acid, phosphoric acid or carbonic acid.
4. The method for safely and non-toxic removing nickel ion impurities in peramivir trihydrate intermediate M9 according to claim 1, wherein the method comprises the following steps: the specific steps of the step E are as follows: slowly cooling the organic phase to 15-25 ℃, continuously stirring at 15-25 ℃, and centrifugally separating precipitated crystals; leaching the filter cake with toluene, centrifuging until no liquid drops drip out, and continuing centrifuging for 1 h; drying, and air-blast drying the filter cake at 40-50 ℃ for 4-6h to finally obtain the refined peramivir trihydrate intermediate M9, namely PLMW-M9.
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