CN110642885A - Polysubstituted phenol phosphate salt and preparation method and application thereof - Google Patents
Polysubstituted phenol phosphate salt and preparation method and application thereof Download PDFInfo
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/12—Esters of phosphoric acids with hydroxyaryl compounds
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- A61P35/00—Antineoplastic agents
Abstract
The invention relates to a polysubstituted phenol phosphate and a preparation method thereof, comprising the following steps: s1: dissolving a polysubstituted phenol compound in an inert organic solvent, adding an acid-binding agent, slowly adding pyrophosphoryl chloride, and after the addition is finished, carrying out heat preservation reaction for 2-24 hours to obtain a polysubstituted phenol monophosphate precursor; s2: adding an organic solvent A into a polysubstituted phenol monophosphate precursor, diluting, dropwise adding an inorganic alkali solution to enable the pH of a water phase to be larger than 7, separating, discarding an organic phase, adjusting the pH of the water phase to be 1, adding an organic solvent B for extraction, combining the organic phases, and concentrating to be dry to obtain polysubstituted phenol monophosphate; s3: neutralizing with alkali liquor, and hydrolyzing to obtain polysubstituted phenol phosphate sodium salt. Compared with the prior art, the invention provides an improvement of a synthesis method of the phosphate ester prodrug of the polysubstituted phenol antitumor drug, has better phosphorylation effect in the synthesis, has simple route and higher purity, and is suitable for industrial production.
Description
Technical Field
The invention relates to a preparation process of a phosphate prodrug, in particular to polysubstituted phenol phosphate and a preparation method and application thereof.
Background
Compared with combretastatin and erianin, the antitumor activity of the stilbene or diphenylethane fluorinated derivatives is remarkably enhanced (CN107365248A, US2012/0046492A1 and CN 103539642). Although these polysubstituted phenol (stilbene and diphenylethane) compounds have stronger antitumor activity, the polysubstituted phenol (stilbene and diphenylethane) compounds have the defects of poor water solubility, poor pharmacokinetics and low bioavailability as the drug development, phosphate groups are introduced on phenolic hydroxyl groups of the polysubstituted phenol compounds to prepare water-soluble phosphate salt prodrugs which have better drug forming properties, the phosphate sodium salt (CA4P) of CA4 has already entered clinical three-phase research, and the development and report of the erianin phosphate sodium salt are reported in China.
The following methods are mainly used for introducing phosphate groups into phenolic hydroxyl groups: 1) phenol with P (O) Cl3After high-temperature reflux, the mixture is neutralized with water to obtain the phenol phosphate with the yield of 70.4 percent. (Freeman H.F&Colver C.W (1938) Synthesis of lithium Phenyl phosphate journal of the American Chemical Society,60(4), 750-751); 2) phenol reacts with phosphoric acid and xylene under reflux to obtain phenol phosphate with low reaction yield (Suga, Akir)a; tsuushima, Tairo, condensation product containing phosphate organic derivative of phenol and aldehyde for dispersion and hydralic composition, JP 2018127542); 3) phenol and phosphorus pentoxide are subjected to reflux reaction to obtain the phenol phosphate with the reaction yield of 65 percent (Tago T, Kuwashiro N)&Nishide H. (2007), Preparation of Acid-Functionalized Poly (phenylene oxide) s and Poly (phenylene sulfone) and TheirProton reduction of bulletin of the Chemical Society of Japan,80(7), 1429) -1434; 4) the phenol reacts with dibenzyl phosphate and then the benzyl group is removed to obtain the phenolic hydroxyl phosphate, the total yield is only 60 percent, the reaction reagent is expensive, the reaction steps are long, the yield is low (Deprez P, Mandine E, Gofflo D, Meuner S,&Lesuisse D.(2002).Small ligands interacting with the phosphotyrosine binding pocket ofthe Src SH2 protein.Bioorganic&medicinal Chemistry Letters,12(9), 1295-); 5) the phenolic hydroxyl group was reacted with diethylphosphorous acid chloride and then the ethyl group was removed with trimethylbromosilane to give phenolic hydroxyl phosphate in a total yield of 64%, expensive reagents, long reaction steps and low yield (Rademann, Joerg, Preparation of Ethyl methyl amine furazan-3-carboxylic acid derivatives for the treatment of cancer, WO 2018065536).
There are two main ways of synthesizing stilbene and diphenylethane phosphate prodrug, one is with phosphorylating reagent ((ButO)2P(O)Cl、P(O)Cl3、P(O)Br3Etc.) and then reacts with alkali to obtain phosphate, the method has higher requirement on the water content in a reaction solvent, and is inevitably accompanied with the production of diphenyl ester byproducts, and the product purification process is complicated and is not beneficial to expanded production (CN 1907989A). Secondly, obtaining corresponding phenol monobenzyl monophosphate by reacting with dibenzyl phosphite, removing benzyl by trimethyl bromosilane, reacting with a large amount of excessive sodium methoxide to remove genotoxic impurity benzyl bromide generated in the debenzylation reaction, carrying out acidification extraction to remove a large amount of inorganic salt, neutralizing an organic phase by alkali after concentrating, adding acetone for cooling and crystallizing to obtain sodium phosphate (CN1706851A), wherein the method can avoid side reaction impurities of diphenyl phosphate, but has the reaction stepThe total yield of the step length is not high, the post-treatment is complex and the like, and dibenzyl phosphite is expensive, and a solvent of carbon tetrachloride is needed in the reaction step of forming the phenol ester.
Therefore, there is a need to develop a production process for preparing sodium phosphate of polysubstituted phenols (diphenylethylene and diphenylethane) with high purity and easy operation under mild reaction conditions, and a corresponding sodium phosphate variety.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide the polysubstituted phenol phosphate salt, the preparation method and the application thereof, wherein the polysubstituted phenol phosphate salt has the advantages of mild reaction conditions, high yield and simple and convenient operation.
The purpose of the invention can be realized by the following technical scheme:
the molecular structural general formula of the polysubstituted phenol phosphate salt is shown as the formula (I):
wherein:
the dotted line represents a bond or is absent;
r is one of methoxyl, ethoxyl, difluoromethoxyl or difluoroethyl.
The preparation method of the polysubstituted phenol phosphate is characterized by comprising the following steps:
s1: dissolving a polysubstituted phenol compound in an inert organic solvent, adding an acid-binding agent, slowly adding pyrophosphoryl chloride, and after the addition is finished, carrying out heat preservation reaction for 2-24 hours to obtain a polysubstituted phenol monophosphate precursor;
s2: adding an organic solvent A into a polysubstituted phenol monophosphate precursor, diluting, dropwise adding an inorganic alkali solution to enable the pH of a water phase to be larger than 7, separating, discarding an organic phase, adjusting the pH of the water phase to be 1, adding an organic solvent B for extraction, combining the organic phases, and concentrating to be dry to obtain polysubstituted phenol monophosphate;
s3: neutralizing with alkali liquor, and hydrolyzing to obtain polysubstituted phenol phosphate sodium salt.
Further, the polysubstituted phenolic compound in S1 is a stilbene or diethylene anti-tumor compound having phenolic hydroxyl group, characterized in that 5-position of the phenolic ring is 3,4, 5-trimethoxystyryl or 3,4, 5-trimethoxyphenethyl substituted, and 2-position is methoxy (OMe), ethoxy (OEt), difluoromethoxy (OCF)2H) Or difluoroethyl (CF)2CH3) And (4) substitution.
Further, the molecular formula of the polysubstituted phenolic compound in S1 is:
further, the molecular formula of the precursor of the polysubstituted phenol monophosphate in S1 is as follows:
further, the molecular formula of the polysubstituted phenol monophosphate in S2 is:
further, neutralization is carried out in S3, and the hydrolysis process is as follows: and (3) dissolving the polysubstituted phenol monophosphate obtained in the step (S2) in tetrahydrofuran, neutralizing one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide or sodium hydride, filtering, washing and drying to obtain the polysubstituted phenol phosphate sodium salt.
Further, neutralization is carried out in S3, and the hydrolysis process is as follows: and (3) dissolving the polysubstituted phenol monophosphate obtained in the step (S2) in a slightly excessive solution of sodium hydroxide, sodium carbonate and sodium bicarbonate, adding excessive acetone, cooling, crystallizing, filtering, washing and drying to obtain the corresponding polysubstituted phenol phosphate sodium salt.
Furthermore, the molar ratio of the polysubstituted phenolic compound in S1 to the pyrophosphoric chloride is 1: 1-1: 10, preferably 1: 1-1: 5, and more preferably 1: 2-1: 5;
the molar ratio of the polysubstituted phenolic compound to the acid-binding agent is 1: 1-1: 14, preferably 1: 2-1: 5;
the reaction temperature is-60 ℃ to 40 ℃, preferably-20 ℃ to 30 ℃, and more preferably-5 ℃ to 30 ℃;
the preferred reaction time is 2 h.
Further, the organic solvent A is one of chloroform, dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether or toluene, and the organic solvent B is dichloromethane or ethyl acetate.
Further, the inert organic solvent is one or more of halogenated alkane, acetate, ether and aromatic hydrocarbon, wherein: the alkyl halide is chloroform, dichloromethane and dichloroethane, preferably chloroform and dichloromethane, more preferably dichloromethane; the acetate is ethyl acetate, methyl acetate and isopropyl acetate, preferably ethyl acetate and isopropyl acetate; the ether solvent is diethyl ether, tetrahydrofuran, dioxane and methyl tert-butyl ether, preferably tetrahydrofuran and methyl tert-butyl ether; the aromatic hydrocarbon solvent is benzene, toluene and polysubstituted benzene, and toluene is preferred.
Further, the acid-binding agent is one or more of pyridines, aromatic amines and trialkylamines, wherein: pyridine solvents include pyridine, 2,4, 6-trimethylpyridine, 2, 6-dimethylpyridine, preferably pyridine; the aromatic amine includes N, N-dimethylaniline, N-diethylaniline, N-diphenylmethylamine and the like, preferably N, N-dimethylaniline; the trialkylamine is trimethylamine, triethylamine, diisopropylethylamine, etc., preferably triethylamine and diisopropylethylamine.
The polysubstituted phenol phosphate in the invention is applied to the phosphate prodrug of the antitumor drug.
Compared with the prior art, the invention is an improvement of the synthesis method of the phosphate ester prodrug of the polysubstituted phenol (stilbene and diphenylethane) antitumor drug, has better phosphorylation effect in the synthesis, has simple route and higher purity, and is suitable for industrial production.
Drawings
FIG. 1 is a flow chart of the preparation of polysubstituted phenol phosphate ester salt of the present invention.
Detailed Description
The invention is described in detail below with reference to the figures and specific embodiments.
Example 1
Synthesis of Compound 1 phosphate
5g of Compound 1(CA4) was weighed out, compound 1 having the formula:
dissolving the raw materials by using 30 ml of chloroform, adding 6 ml of pyrophosphoryl chloride dropwise at 0 ℃ under the protection of nitrogen, immediately adding 6 ml of diisopropylethylamine dropwise, reacting for 2 hours, adding 100 ml of chloroform for dilution, then adding 100 ml of saturated sodium bicarbonate solution dropwise, stirring for 30 minutes, separating, discarding an organic phase, adjusting the pH of an aqueous phase to about 1 by using hydrochloric acid, stirring for 30 minutes, extracting for three times by using 450 ml of dichloromethane, combining extracts, drying by using anhydrous sodium sulfate, and evaporating and concentrating under reduced pressure to remove chloroform to obtain a compound 1 phosphate, 5.3g of white oily foam, and the yield of 84.6%.
5g of compound 1 phosphate is weighed, 2.1 equivalents of sodium hydroxide solution are added for reaction, and after concentration, the compound 1 phosphate sodium salt is recrystallized by acetone to obtain 5.1g of compound 1 phosphate sodium salt, and the yield is 91.8%.
The molecular formula of the sodium phosphate salt of the compound 1 is as follows:
example 2
Synthesis of Compound 2 sodium phosphate salt
Weighing 5g of compound 2 (erianin), wherein the molecular formula of the compound 2 is as follows:
dissolving the raw materials by using 30 ml of dichloromethane, adding 6 ml of pyrophosphoryl chloride dropwise at 0 ℃ under the protection of nitrogen, immediately adding 6 ml of pyridine dropwise, reacting for 2 hours, adding 100 ml of dichloromethane for dilution, then adding 100 ml of saturated sodium bicarbonate solution dropwise, stirring for 30 minutes, separating, removing an organic phase, adjusting the pH of an aqueous phase to about 1 by using hydrochloric acid, stirring for 30 minutes, extracting for three times by using 450 ml of ethyl acetate, combining extract liquor, drying by using anhydrous sodium sulfate, and evaporating and concentrating under reduced pressure to remove the ethyl acetate to obtain a compound 2 phosphate, wherein the white oily foam is 5.3g, and the yield is 84.7%.
5g of compound 2 phosphate is added into 1.2 equivalent of 1M sodium carbonate solution to be stirred and dissolved, then 5 times volume of acetone is added, and the mixture is cooled, crystallized, filtered and dried to obtain 5.2g of compound 2 phosphate sodium salt with the yield of 93.7 percent.
The molecular formula of the sodium phosphate salt of the compound 2 is as follows:
example 3
Synthesis of compound 3 phosphoric acid ester sodium salt
Weighing 5g of compound 3, wherein the molecular formula of compound 1 is as follows:
dissolving the raw materials by using 30 ml of ethyl acetate, adding 6 ml of pyrophosphoryl chloride dropwise at 0 ℃ under the protection of nitrogen, immediately adding 6 ml of N, N-dimethylaniline dropwise, reacting for 2 hours, adding 100 ml of ethyl acetate for dilution, then adding 100 ml of saturated sodium bicarbonate solution dropwise, stirring for 30 minutes, separating liquid, discarding an organic phase, adjusting the pH of an aqueous phase to about 1 by using hydrochloric acid, stirring for 30 minutes, extracting for three times by using 450 ml of ethyl acetate, combining extract liquor, drying by using anhydrous sodium sulfate, evaporating and concentrating under reduced pressure to remove the ethyl acetate, and obtaining the compound 3 phosphate, wherein the white oily foam is 5.6g, and the yield is 88.6%.
Adding 5g of compound 3 phosphate into 2.2 equivalent of 1M sodium bicarbonate solution, stirring for 1h, adding 5 times volume of acetone, cooling, crystallizing, filtering, and drying to obtain 5.2g of compound 3 phosphate sodium salt with yield of 93.3%.
The molecular formula of the sodium phosphate salt of the compound 3 is as follows:
example 4
Synthesis of Compound 4 sodium phosphate salt
Weighing 5g of compound 4, wherein the molecular formula of compound 1 is as follows:
dissolving isopropyl acetate 30 ml, adding pyrophosphoryl chloride 6 ml dropwise at 0 ℃ under the protection of nitrogen, immediately adding N, N-dimethylaniline 6 ml dropwise, reacting for 2 hours, adding isopropyl acetate 100 ml for dilution, adding saturated sodium bicarbonate solution 100 ml dropwise, stirring for 30 minutes, separating liquid, discarding an organic phase, adjusting the pH of an aqueous phase to about 1 by hydrochloric acid, stirring for 30 minutes, extracting with isopropyl acetate 450 ml for three times, combining extracts, drying with anhydrous sodium sulfate, evaporating and concentrating under reduced pressure to remove isopropyl acetate, and obtaining a compound 4 phosphate, wherein the white oily foam is 5.3g, and the yield is 86.4%.
5g of compound 4 phosphate is dissolved in anhydrous tetrahydrofuran, 2.1 equivalents of sodium methoxide is added, stirring is carried out for 2 hours, filtering and drying are carried out, thus obtaining 5.1g of compound 4 phosphate sodium salt with the yield of 92.6 percent.
The molecular formula of the sodium phosphate salt of the compound 4 is as follows:
example 5
Synthesis of Compound 5 sodium phosphate salt
Weighing 5g of compound 5, wherein the molecular formula of compound 1 is as follows:
dissolving the mixture by using 30 ml of tetrahydrofuran, adding 6 ml of pyrophosphoryl chloride dropwise at 0 ℃ under the protection of nitrogen, immediately adding 6 ml of triethylamine dropwise, reacting for 2 hours, adding 100 ml of tetrahydrofuran for dilution, then adding 100 ml of saturated sodium bicarbonate solution dropwise, stirring for 30 minutes, separating liquid, removing an organic phase, adjusting the pH of an aqueous phase to about 1 by using hydrochloric acid, stirring for 30 minutes, extracting for three times by using 450 ml of ethyl acetate, combining extract liquor, drying by using anhydrous sodium sulfate, and evaporating and concentrating under reduced pressure to remove the ethyl acetate to obtain a compound 5 phosphate, 5.5g of white oily foam, and the yield of 89.7%.
5g of compound 5 phosphate is dissolved in anhydrous tetrahydrofuran, 2.1 equivalents of sodium ethoxide are added, the mixture is stirred for 2 hours at room temperature, and then the mixture is filtered and dried to obtain 5.1g of compound 5 phosphate sodium salt, wherein the yield is 92.3%.
The molecular formula of the sodium phosphate salt of the compound 5 is as follows:
example 6
Synthesis of compound 6 sodium phosphate salt
Weighing 5g of compound 6, wherein the molecular formula of compound 1 is as follows:
dissolving the raw materials by using 30 ml of methyl tert-butyl ether, adding 6 ml of pyrophosphoryl chloride dropwise at 0 ℃ under the protection of nitrogen, immediately adding 6 ml of N, N-dimethylaniline dropwise, reacting for 2 hours, adding 100 ml of methyl tert-butyl ether for dilution, then adding 100 ml of saturated sodium bicarbonate solution dropwise, stirring for 30 minutes, separating liquid, discarding an organic phase, adjusting the pH of an aqueous phase to about 1 by using hydrochloric acid, stirring for 30 minutes, extracting for three times by using 450 ml of ethyl acetate, combining extract liquor, drying by using anhydrous sodium sulfate, evaporating and concentrating under reduced pressure to remove the ethyl acetate, and obtaining a compound 6 phosphate, wherein 5.4g of white oily foam is obtained, and the yield is 87.9%.
5g of the compound 6 phosphate was dissolved in anhydrous tetrahydrofuran, and 2.2 equivalents of sodium hydrogen solution was added to react, followed by concentration and recrystallization from acetone to obtain 5.1g of the compound 6 phosphate salt with a yield of 92.6%.
The molecular formula of the sodium phosphate salt of the compound 6 is as follows:
example 7
Synthesis of compound 7 sodium phosphate salt
Weighing 5g of compound 7, wherein the molecular formula of compound 1 is as follows:
dissolving the raw materials in 30 ml of toluene, adding 6 ml of pyrophosphoryl chloride dropwise at 0 ℃ under the protection of nitrogen, immediately adding 6 ml of N, N-dimethylaniline dropwise, reacting for 2 hours, adding 100 ml of toluene for dilution, then adding 100 ml of saturated sodium bicarbonate solution dropwise, stirring for 30 minutes, separating, discarding an organic phase, adjusting the pH of an aqueous phase to about 1 by using hydrochloric acid, stirring for 30 minutes, extracting for three times by using 450 ml of ethyl acetate, combining extract liquor, drying by using anhydrous sodium sulfate, and then carrying out reduced pressure evaporation and concentration to remove the ethyl acetate to obtain a compound 7 phosphate, wherein the white oily foam is 5.5g, and the yield is 89.6%.
5g of the compound 6 phosphate was dissolved in anhydrous tetrahydrofuran, and 2.2 equivalents of sodium hydrogen solution was added to react, followed by concentration and recrystallization from acetone to obtain 5.1g of the compound 6 phosphate salt with a yield of 92.4%.
The molecular formula of the sodium phosphate salt of the compound 7 is as follows:
it should be noted that the above mentioned embodiments are only preferred embodiments of the present invention, and not intended to limit the scope of the present invention, which is defined in the appended claims, and any other technical entity or method implemented by others is exactly the same as or equivalent to the one defined in the claims, and all changes that come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
Claims (10)
1. A polysubstituted phenol phosphate is characterized in that the molecular structural general formula is as shown in formula (I):
wherein:
the dotted line represents a bond or is absent;
r is one of methoxyl, ethoxyl, difluoromethoxyl or difluoroethyl.
2. A process for the preparation of polysubstituted phenol phosphate salts according to claim 1, characterized by the following steps:
s1: dissolving a polysubstituted phenol compound in an inert organic solvent, adding an acid-binding agent, slowly adding pyrophosphoryl chloride, and after the addition is finished, carrying out heat preservation reaction for 2-24 hours to obtain a polysubstituted phenol monophosphate precursor;
s2: adding an organic solvent A into a polysubstituted phenol monophosphate precursor, diluting, dropwise adding an inorganic alkali solution to enable the pH of a water phase to be larger than 7, separating, discarding an organic phase, adjusting the pH of the water phase to be 1, adding an organic solvent B for extraction, combining the organic phases, and concentrating to be dry to obtain polysubstituted phenol monophosphate;
s3: neutralizing with alkali liquor, and hydrolyzing to obtain polysubstituted phenol phosphate sodium salt.
3. A process for the preparation of the polysubstituted phenol phosphate according to claim 2, wherein the polysubstituted phenolic compound of S1 has the formula:
4. a method for preparing polysubstituted phenol phosphate according to claim 2, wherein the molecular formula of the precursor polysubstituted phenol phosphate in S1 is:
5. a process for preparing polysubstituted phenol phosphates according to claim 2 wherein the polysubstituted phenol monophosphates of S2 have the formula:
6. a process for the preparation of polysubstituted phenol phosphate salts according to claim 2, characterized in that the neutralization in S3 is carried out by the following hydrolysis steps: and (3) dissolving the polysubstituted phenol monophosphate obtained in the step (S2) in tetrahydrofuran, neutralizing one or more of sodium methoxide, sodium ethoxide, sodium tert-butoxide or sodium hydride, filtering, washing and drying to obtain the polysubstituted phenol phosphate sodium salt.
7. A process for the preparation of polysubstituted phenol phosphate salts according to claim 2, characterized in that the neutralization in S3 is carried out by the following hydrolysis steps: and (3) dissolving the polysubstituted phenol monophosphate obtained in the step (S2) in a slightly excessive solution of sodium hydroxide, sodium carbonate and sodium bicarbonate, adding excessive acetone, cooling, crystallizing, filtering, washing and drying to obtain the corresponding polysubstituted phenol phosphate sodium salt.
8. The preparation method of the polysubstituted phenol phosphate salt according to claim 2, wherein the molar ratio of the polysubstituted phenolic compound to the pyrophosphoryl chloride in S1 is 1: 1-1: 10, the molar ratio of the polysubstituted phenolic compound to the acid-binding agent is 1: 1-1: 14, and the reaction temperature is-60 ℃ to 40 ℃.
9. A method for preparing the polysubstituted phenol phosphate according to claim 2, wherein the organic solvent a is one of chloroform, dichloromethane, ethyl acetate, isopropyl acetate, tetrahydrofuran, methyl tert-butyl ether or toluene, and the organic solvent B is dichloromethane or ethyl acetate.
10. Use of polysubstituted phenol phosphate according to claim 1 in the manufacture of a prodrug of an antineoplastic agent.
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| CN112480165A (en) * | 2020-11-05 | 2021-03-12 | 上海应用技术大学 | A crystal form of polysubstituted diphenylethane phosphate sodium salt EBTP and preparation method thereof |
| CN115429769A (en) * | 2022-07-08 | 2022-12-06 | 上海华理生物医药股份有限公司 | EBTP capsule and preparation method thereof |
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| CN112480165A (en) * | 2020-11-05 | 2021-03-12 | 上海应用技术大学 | A crystal form of polysubstituted diphenylethane phosphate sodium salt EBTP and preparation method thereof |
| CN115429769A (en) * | 2022-07-08 | 2022-12-06 | 上海华理生物医药股份有限公司 | EBTP capsule and preparation method thereof |
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