CN111233689A - 13Purification method and preparation method of C-methaoxetine - Google Patents

13Purification method and preparation method of C-methaoxetine Download PDF

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CN111233689A
CN111233689A CN202010205262.7A CN202010205262A CN111233689A CN 111233689 A CN111233689 A CN 111233689A CN 202010205262 A CN202010205262 A CN 202010205262A CN 111233689 A CN111233689 A CN 111233689A
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methacetin
crude product
resin
purifying
purification
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CN111233689B (en
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龚爱华
白玉杰
图布新
刘伟
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Jiangsu Huagen Tailai Biotechnology Co ltd
Beijing Richen Force Science & Technology Co ltd
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Beijing Richen Force Science & Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
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    • C07C231/00—Preparation of carboxylic acid amides
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Abstract

The invention relates to the technical field of chemical medicine purification, in particular to a method for purifying a compound13A method for purifying C methaoxetine and a preparation method thereof.13The purification method of C methacetin comprises the following steps:13dissolving the C methacetin crude product in a solvent, mixing with ionic resin and active carbon, performing solid-liquid separation, and collecting liquid; and (4) removing the solution of the liquid, and then recrystallizing. The invention uses the ionic resin and the active carbon to treat the crude product, removes impurities and decolors, and can effectively remove impurities13Impurities are introduced in the synthesis process of C methacetin, so that the purity of a purified product is improved; especially for passing through13Prepared by the reaction of C-methyl p-toluenesulfonate and paracetamol13The C-methacetin crude product can greatly remove impurities in the C-methacetin crude product, and the purity of the product is improvedAnd yield of p13The research and development and application of the C methaoxetine are of great significance.

Description

13Purification method and preparation method of C-methaoxetine
Technical Field
The invention relates to the technical field of chemical medicine purification, in particular to a method for purifying a compound13A method for purifying C methaoxetine and a preparation method thereof.
Background
13The synthesis method of the C-methacetin as a liver function detection diagnostic reagent is multiple, and mainly comprises the following four synthesis routes.
Route 1:
Figure BDA0002419162160000011
route 2:
Figure BDA0002419162160000012
route 3:
Figure BDA0002419162160000021
route 4:
Figure BDA0002419162160000022
the crude products obtained by different synthesis methods contain different impurities. The existence of impurities is harmful to human body when the medicine is clinically used, and how to aim at different synthetic routes13The purification of C-methacetin to remove impurities is an urgent problem to be solved.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first purpose of the invention is to provide13Purification process for C-methacetin with high efficiency removal13C impurities in the crude product of the methaoxetine.
A second object of the present invention is to provide13Process for the preparation of C-methacetin, the process for the preparation of the same13The purification treatment of the C-methacetin crude product can further improve the quality13Purity of C methacetin.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
13the purification method of C methacetin comprises the following steps:
13dissolving the C methacetin crude product in a solvent, mixing with ionic resin and active carbon, performing solid-liquid separation, and collecting liquid;
and (4) removing the solution of the liquid, and then recrystallizing.
According to the invention13The purification method of C-methacetin uses ion resin and active carbon to treat the crude product, removes impurities and decolors, and can effectively remove impurities13Impurities are introduced in the synthesis process of the C methacetin, so that the purity of a purified product is improved.
In a preferred embodiment of the present invention, the ionic resin includes any one or more of a strongly acidic cationic resin, a strongly basic anionic resin, a weakly acidic cationic resin and a weakly basic anionic resin. More preferably, the ionic resin comprises a weakly acidic cationic resin and a weakly basic anionic resin; the mass ratio of the weakly acidic cation resin to the weakly basic anion resin is 1: 1-2.
In a preferred embodiment of the present invention, the particle size of the ionic resin is 0.40 to 0.70 mm.
In a preferred embodiment of the invention, the ionic resin comprises any one or more of D113, D301, 732 and 717.
By using the above specific ionic resins, can be used for13The C-methacetin crude product realizes high decoloration and impurity removal effects and is obtained by purification13The product C is good in color, high in yield and purity and suitable for industrial production.
In a preferred embodiment of the invention, the ionic resin is pre-treated prior to use; the pretreatment method comprises the following specific steps: and sequentially carrying out water washing, alkali washing, water washing, acid washing and water washing on the ionic resin. Wherein the step of alkali washing comprises the following steps: soaking the raw materials in 5-10% sodium hydroxide aqueous solution and washing the raw materials; the pickling step comprises: soaking the fabric in 1-2 wt% hydrochloric acid solution and washing.
In a preferred embodiment of the present invention, the mixing conditions include: the temperature is-15 to 80 ℃, and the time is 5 to 9 hours. Preferably, the conditions of the mixing treatment include: the temperature is 30-80 ℃, and the time is 6-8 h.
In a preferred embodiment of the present invention, the above13The mass ratio of the C methacetin crude product to the ion resin to the activated carbon is 1: 0.5-3: 0.1-2, and preferably 1: 1-1.5: 0.9-1.5.
As in the case of the different embodiments,13the mass ratio of the crude C methaoxetine product to the ion resin can be 1: 0.5, 1: 0.8, 1: 1, 1: 1.2, 1: 1.5, 1: 1.8, 1: 2, 1: 2.2, 1: 2.5, 1: 2.8, 1: 3 and the like;13the mass ratio of the crude C methaoxetine product to the activated carbon can be 1: 0.1, 1: 0.5, 1: 0.9, 1: 1, 1: 1.2, 1: 1.5, 1: 1.6, 1: 2 and the like. In particular, the method comprises the following steps of,13the mass ratio of the crude C methaoxetine product to the ion resin to the activated carbon can be 1: 1.2: 1, 1: 1.6, 1: 1.5: 1.2 and the like.
In a preferred embodiment of the present invention, the solvent comprises one or more of ethyl acetate, dichloromethane, ethanol, methanol, toluene, preferably ethyl acetate.
In a preferred embodiment of the present invention, the above13The dosage ratio of the C methacetin crude product to the solvent is 1g to (2-5) mL.
In a preferred embodiment of the present invention, the solvent used for recrystallization includes any one or two of dichloromethane, chloroform, ethanol, methanol, isopropanol, tert-butanol, ethyl acetate, ethyl formate, methyl acetate, methyl formate, tert-butyl acetate, toluene, acetonitrile, tetrahydrofuran and water.
In a preferred embodiment of the present invention, the above13The C-methacetin crude product is prepared by13C, methyl p-toluenesulfonate and acetaminophen react to prepare the compound.
The above preparation corresponds to the synthesis scheme in scheme 2. In scheme 2, the main reactions are13C methanol and p-toluenesulfonyl chloride are generated in alkaline environment13C methyl p-toluenesulfonate, then reacting with alkalized paracetamol to generate13C, a crude product of the methaoxetine. In this reaction route, the crude product is dark yellow to dark brown in color and contains many impurities.13The main impurities of the C-mesaoxetine crude product comprise starting material acetaminophen and intermediate13C-methyl p-toluenesulfonate, N- (4-methoxyphenyl) -N-methylacetamide as impurity, N- (4-hydroxyphenyl) -N-methylacetamide as impurity, p-acetylaminophenetole as impurity,13C, ethyl p-toluenesulfonate, a degradation product p-anisidine and the like. Wherein13C methyl p-toluenesulfonate and13the C-ethyl tosylate is a genotoxic impurity, has high toxicity to human bodies and is harmful to the human bodies in clinical use.
The invention is prepared by aiming at the route13The C-mesaoxetine crude product is purified, ion resin and active carbon are used for matching, impurity removal and decoloration are carried out, and then recrystallization is carried out, so that the obtained product can be greatly improved13The yield and purity of the C methacetin product can be improved, and the color can be removed.
The invention also provides a13The preparation method of C methaoxetine, which comprises adopting any one of the purification methods described above to prepare13And C, purifying the crude product of the methacetin.
When said13The C-methacetin crude product is prepared by13When the C-methyl p-toluenesulfonate is prepared by reacting with acetaminophen, the obtained product can be further improved13Purity and yield of the C methacetin product.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention13The purification method of C-methacetin uses ion resin and active carbon to treat the crude product, removes impurities and decolors, and can effectively remove impurities13Beauty of CImpurities are introduced in the synthesis process of the paroxetine, so that the purity of a purified product is improved; especially for passing through13Prepared by the reaction of C-methyl p-toluenesulfonate and paracetamol13The C-methacetin crude product can greatly remove impurities in the C-methacetin crude product, improve the yield and purity of the product, and reduce the production cost13The research and development and application of the C methaoxetine are of great significance.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and other drawings can be obtained by those skilled in the art without creative efforts.
FIG. 1 shows the results of example 1 of the present invention13C, liquid chromatogram of the crude methacetin product;
FIG. 2 shows a sample obtained after purification according to example 1 of the present invention13And C, liquid chromatogram of the methaoxetine product.
Detailed Description
The technical solutions of the present invention will be clearly and completely described below with reference to the accompanying drawings and the detailed description, but those skilled in the art will understand that the following described embodiments are some, not all, of the embodiments of the present invention, and are only used for illustrating the present invention, and should not be construed as limiting the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In each embodiment of the invention13The purity of the C methacetin is detected by using a high performance liquid chromatography, and the detection conditions are as follows:
a chromatographic column: column Kromasil (100-5-C184.6 x 250mm or equivalent performance column);
flow rate: 0.8 mL/min-1；
Detection wavelength: 233 nm;
column temperature: 35 ℃;
sample introduction amount: 5 mu L of the solution;
mobile phase: phosphate buffered water/acetonitrile (v/v) ═ 80/20.
The ionic resins adopted in the embodiment all adopt water washing, alkali washing, water washing, acid washing and water washing in sequence; wherein, the step of alkali washing comprises the following steps: soaking the raw materials in a sodium hydroxide aqueous solution with the mass fraction of 5% and then washing the raw materials; the pickling step comprises: soaking the fabric in 1% hydrochloric acid water solution and washing the fabric.
Example 1
Of the present embodiment13The preparation method of the C-methacetin crude product comprises the following steps:
(1) 400g of a solid sodium hydroxide was weighed and dissolved completely in 2000mL of pure water with stirring to obtain an aqueous solution of sodium hydroxide. 500g of p-toluenesulfonyl chloride, 100g of anhydrous13Adding methanol and 1100.0mL of anhydrous tetrahydrofuran into the reaction kettle, stirring to completely dissolve, adding the aqueous solution of sodium hydroxide, and controlling the temperature to be about 25 ℃ to react for 1 hour.
(2) After the reaction in the step (1) is finished, adding 200mL of water to quench the reaction, then adding 800mL of pure water and 1000mL of ethyl acetate, stirring, standing for layering, collecting an organic phase, stirring and washing the organic phase with a dilute sodium hydroxide aqueous solution and a saturated sodium chloride aqueous solution in sequence, drying, and concentrating to obtain the compound13C methyl p-toluenesulfonate.
(3) Prepared by13650.0g of methyl p-toluenesulfonate C was dissolved in 2000mL of anhydrous tetrahydrofuran to obtain an intermediate solution. Adding 8000mL of anhydrous tetrahydrofuran and 900g of p-acetamidophenol into a reaction kettle, starting stirring for dissolving, adding 180g of sodium hydride solid, uniformly stirring, dropwise adding the prepared intermediate solution, continuing to react for 2-6 hours after dropwise adding, slowly adding water for quenching reaction after the reaction is finished, adding ethyl acetate for separating liquid, collecting an organic phase, sequentially using a sodium hydroxide aqueous solution and pure water to separate the liquid from the organic phaseWashing with saturated saline solution, drying, and concentrating to obtain light yellow13C, a crude product of the methaoxetine. The purity of the crude product is 88.1 percent, and the main impurities are acetaminophen and the like.
Prepared by the method13The liquid chromatogram of the crude C-methacetin is shown in figure 1.
The embodiment provides13The purification method of C methacetin comprises the following steps:
taking the product obtained by the above preparation1350g of a C methacetin crude product is completely dissolved by 150mL of normal-temperature ethyl acetate, 50g of activated carbon, 20g of pretreated cation weak-acid D113 type exchange resin and 40g of pretreated anion weak-base D301 type resin are added, the mixture is heated to reflux and kept for 7 hours, and the mixture is cooled, filtered and concentrated to obtain a solid. Adding ethyl acetate into the solid, heating to reflux and dissolve the solid clearly, slowly cooling to 0-10 ℃ after dissolving, carrying out heat preservation and crystallization for 4.5-5.5 hours, carrying out reduced pressure filtration, and leaching the filter cake with 20mL of cold (0-minus 5 ℃) ethyl acetate. Vacuum drying the filtered filter cake in a reduced pressure drying oven at 55 + -5 deg.C for 7 + -0.5 h to obtain 42g white solid powder13C methacetin, yield 84%.
Purified by the above method13The liquid chromatogram of the C methacetin product is shown in figure 2. Wherein, the detection conditions of FIG. 1 and FIG. 2 are the same, and the detection instruments are slightly different, so that the retention time is slightly different.
Example 2
Of the present embodiment13C-Meoxetine crude product prepared by the method of reference example 113The purity of the C methacetin crude product is 88.1%, and the main impurities are acetaminophen and the like.
The embodiment provides13The purification method of C methacetin comprises the following steps:
taking the product obtained by the above preparation1350g of C-methacetin crude product is completely dissolved by 150mL of normal-temperature ethyl acetate, 80g of activated carbon, 30g of pretreated cation weak-acid 732 type exchange resin and 50g of pretreated anion weak-base 717 type resin are added, the mixture is heated to reflux for 7 +/-0.5 h, cooled, filtered and condensed to obtain solid. Adding ethyl acetate into the solid, heating to reflux and dissolve the solid clearly, slowly cooling to 0-10 ℃ after dissolving, carrying out heat preservation and crystallization for 5 hours, and carrying out reduced pressure filtration. Vacuum drying the filtered filter cake in a vacuum drying oven at 55 + -5 deg.C for 7 + -0.5 h to obtain 41g white solid powder13C methacetin, yield 82%.
Example 3
Of the present embodiment13C-Meoxetine crude product prepared by the method of reference example 113The purity of the C methacetin crude product is 88.1%, and the main impurities are acetaminophen and the like.
The embodiment provides13The purification method of C methacetin comprises the following steps:
taking the product obtained by the above preparation1350g of C-methacetin crude product is completely dissolved by 150mL of normal-temperature ethyl acetate, 60g of activated carbon, 25g of pretreated cation weak-acid D113 type exchange resin and 50g of pretreated anion weak-base 717 type resin are added, the mixture is heated to reflux for 7 +/-0.5 h, and the mixture is cooled, filtered and concentrated to obtain a solid. Adding ethyl acetate into the solid, heating to reflux and dissolve the solid clearly, slowly cooling to 0-10 ℃ after dissolving, carrying out heat preservation and crystallization for 5 hours, and carrying out reduced pressure filtration. Vacuum drying the filtered filter cake in a reduced pressure drying oven at 55 + -5 deg.C for 7 + -0.5 h to obtain 42g white solid powder13C methacetin, yield 84%.
Example 4
Of the present embodiment13C-Meoxetine crude product prepared by the method of reference example 113The purity of the C methacetin crude product is 88.1%, and the main impurities are acetaminophen and the like.
The embodiment provides13The purification method of C methacetin comprises the following steps:
taking the product obtained by the above preparation1350g of a C methacetin crude product is completely dissolved by 150mL of normal-temperature ethyl acetate, 100g of activated carbon, 25g of pretreated cation weak-acid D113 type exchange resin and 50g of pretreated anion weak-base D301 type resin are added, the mixture is heated to reflux and kept for 7 +/-0.5 h, and the mixture is cooled, filtered and concentrated to obtain a solid. Adding acetic acid B into the solidHeating the ester until the ester is refluxed and dissolved, slowly cooling the ester to 0-10 ℃ after dissolution, carrying out heat preservation and crystallization for 5 hours, and carrying out reduced pressure filtration. Vacuum drying the filtered filter cake in a reduced pressure drying oven at 55 + -5 deg.C for 7 + -0.5 h to obtain 39.2g white solid powder13C methacetin, yield 78.4%.
Example 5
Of the present embodiment13C-Meoxetine crude product prepared by the method of reference example 113The purity of the C methacetin crude product is 88.1%, and the main impurities are acetaminophen and the like.
The embodiment provides13The purification method of C methacetin comprises the following steps:
taking the product obtained by the above preparation1350g of a C methacetin crude product is completely dissolved by 150mL of normal-temperature ethyl acetate, 50g of activated carbon, 50g of pretreated cation weak-acid D113 type exchange resin and 100g of pretreated anion weak-base D301 type resin are added, the mixture is heated until reflux is maintained for 7 +/-0.5 h, and the mixture is cooled, filtered and concentrated to obtain a solid. Adding ethyl acetate into the solid, heating to reflux and dissolve the solid clearly, slowly cooling to 0-10 ℃ after dissolving, carrying out heat preservation and crystallization for 5 hours, and carrying out reduced pressure filtration. Vacuum drying the filtered filter cake in a vacuum drying oven at 55 + -5 deg.C for 7 + -0.5 h to obtain 37.6g white solid powder13C methacetin, yield 75.2%.
Example 6
Of the present embodiment13C-Meoxetine crude product prepared by the method of reference example 113The purity of the C methacetin crude product is 88.1%, and the main impurities are acetaminophen and the like.
The embodiment provides13The purification method of C methacetin comprises the following steps:
taking the product obtained by the above preparation13And (3) completely dissolving 50g of the C methacetin crude product in 150mL of normal-temperature ethyl acetate, adding 50g of activated carbon and 60g of pretreated cation weak-acid D113 type exchange resin, heating until reflux is maintained for 7 +/-0.5 h, cooling, filtering and condensing to obtain a solid. Adding ethyl acetate into the solid, heating to reflux and dissolve the solid clearly, slowly cooling to 0-10 ℃ after dissolving, and performing heat preservation and separationCrystallize for 5 hours, filter under reduced pressure. Vacuum drying the filtered filter cake in a reduced pressure drying oven at 55 + -5 deg.C for 7 + -0.5 h to obtain 43g white solid powder13C methacetin in 86% yield.
Example 7
Of the present embodiment13C-Meoxetine crude product prepared by the method of reference example 113The purity of the C methacetin crude product is 88.1%, and the main impurities are acetaminophen and the like.
The embodiment provides13The purification method of C methacetin comprises the following steps:
taking the product obtained by the above preparation13And (3) completely dissolving 50g of the C methacetin crude product in 150mL of normal-temperature ethyl acetate, adding 50g of activated carbon and 60g of pretreated anionic weakly-alkaline D301 type resin, heating to reflux for 7 +/-0.5 h, cooling, filtering and condensing to obtain a solid. Adding ethyl acetate into the solid, heating to reflux and dissolve the solid clearly, slowly cooling to 0-10 ℃ after dissolving, carrying out heat preservation and crystallization for 5 hours, and carrying out reduced pressure filtration. Vacuum drying the filtered filter cake in a vacuum drying oven at 55 + -5 deg.C for 7 + -0.5 h to obtain 41.5g white solid powder13C methacetin, yield 83%.
Comparative example 1
Comparative example 113C-Meoxetine crude product prepared by the method of reference example 113The purity of the C methacetin crude product is 88.1%, and the main impurities are acetaminophen and the like.
Comparative example 1 provides13The purification method of C methacetin comprises the following steps:
the product obtained in example 1 was taken13And (3) completely dissolving 50g of the C methacetin crude product in 150mL of normal-temperature ethyl acetate, adding 50g of activated carbon, heating to reflux for 7 +/-0.5 h, cooling, filtering and concentrating to obtain a solid. Adding ethyl acetate into the solid, heating to reflux and dissolve the solid clearly, slowly cooling to 0-10 ℃ after dissolving, carrying out heat preservation and crystallization for 5 hours, and carrying out reduced pressure filtration. Vacuum drying the filtered filter cake in a reduced pressure drying oven at 55 + -5 deg.C for 7 + -0.5 h to obtain 41g of light yellow solid powder13C methacetin, yield 82%.
Comparative example 2
Comparative example 2 the purification process of example 1 was referenced, except that no activated carbon was added. Preparation 43g of a pale yellow solid powder13C methacetin in 86% yield.
Experimental example 1
For comparative purposes, the purification methods of the examples and comparative examples of the present invention13Purity of C-Meoxetine product, etc., crude product and obtained13The impurity condition and purity of the C methacetin product are detected, and the test results are shown in tables 1 and 2.
TABLE 113Impurity and purity test result of C-methacetin crude product and purified product
Figure BDA0002419162160000111
TABLE 213Purity and color test results of C-methacetin crude product and purified product
Figure BDA0002419162160000112
Figure BDA0002419162160000121
According to the invention13The purification method of C-methacetin uses ion resin and active carbon to treat the crude product, removes impurities and decolors, and can effectively remove impurities13Impurities are introduced in the synthesis process of C methacetin, so that the purity of a purified product is improved; especially for passing through13Prepared by the reaction of C-methyl p-toluenesulfonate and paracetamol13The C-methacetin crude product can greatly remove impurities in the C-methacetin crude product, and the yield and the purity of the product are improved.
Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and the modifications or the substitutions do not make the essence of the corresponding technical solutions depart from the scope of the technical solutions of the embodiments of the present invention.

Claims (10)

1.13The method for purifying C methacetin is characterized by comprising the following steps:
13dissolving the C methacetin crude product in a solvent, mixing the solution with ionic resin and active carbon, and performing solid-liquid separation to collect liquid;
and (4) removing the solution of the liquid, and then recrystallizing.
2. The method of claim 113The method for purifying the C methacetin is characterized in that the ionic resin comprises any one or more of strong acid cation resin, strong base anion resin, weak acid cation resin and weak base anion resin.
3. The method of claim 113The purification method of C methacetin is characterized in that the particle size of the ionic resin is 0.40-0.70 mm;
preferably, the ionic resin comprises any one or more of D113, D301, 732, and 717.
4. The method of claim 113The purification method of C methacetin is characterized in that the ion resin is pretreated before use; the pretreatment method comprises the steps of carrying out alkali washing and acid washing on the isolated resin;
preferably, the isolated resin is subjected to water washing, alkali washing, water washing, acid washing and water washing in this order.
5. The method of claim 113A method for purifying C methacetin, characterized in that the conditions of the mixing treatment comprise: the temperature is-15 to 80 ℃, and the time is 5 to 9 hours;
preferably, the conditions of the mixing treatment include: the temperature is 30-80 ℃, and the time is 6-8 h.
6. The method of any one of claims 1-513A process for the purification of C-methaoxetine13The mass ratio of the C methacetin crude product to the ion resin to the active carbon is 1: 0.5-3: 0.1-2;
preferably, the13The mass ratio of the C methacetin crude product to the ion resin to the active carbon is 1: 1 (1-1.5) to 0.9-1.5.
7. The method of claim 113The method for purifying the C methacetin is characterized in that the solvent comprises one or more of ethyl acetate, dichloromethane, ethanol, methanol and toluene;
preferably, the13The dosage ratio of the C methacetin crude product to the solvent is 1g to (2-5) mL.
8. The method of claim 113The method for purifying C methacetin is characterized in that the solvent adopted by recrystallization comprises any one or two of dichloromethane, chloroform, ethanol, methanol, isopropanol, tert-butyl alcohol, ethyl acetate, ethyl formate, methyl acetate, methyl formate, tert-butyl acetate, toluene, acetonitrile, tetrahydrofuran and water.
9. The method of claim 113A process for the purification of C-methaoxetine13The C-methacetin crude product is prepared by13C, methyl p-toluenesulfonate and acetaminophen react to prepare the compound.
10.13A process for the preparation of C-methaoxetine, comprising subjecting a mixture of claim 1 to 9 to the purification process13And C, purifying the crude product of the methacetin.
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CN115856105A (en) * 2021-09-26 2023-03-28 北京华亘安邦科技有限公司 Analysis method of p-anisidine and C13 methacetin as C13 methacetin impurity reference substance

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