CN116947600B - Preparation method of 2-isopropyl valeric acid as valproic acid process impurity - Google Patents

Preparation method of 2-isopropyl valeric acid as valproic acid process impurity Download PDF

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CN116947600B
CN116947600B CN202310841425.4A CN202310841425A CN116947600B CN 116947600 B CN116947600 B CN 116947600B CN 202310841425 A CN202310841425 A CN 202310841425A CN 116947600 B CN116947600 B CN 116947600B
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isopropyl
acid
preparation
bromide
valeric acid
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CN116947600A (en
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叶姣
杨贞皓
唐叶绿
李明芳
段世辉
胡艾希
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Hunan Province Xiangzhong Pharmaceutical Co ltd
Hunan University
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation

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Abstract

The invention relates to an economical preparation method of 2-isopropyl valeric acid atom shown in chemical structural formula C, which comprises the following steps: the method is characterized in that propionyl acetate and 2-chloropropane are catalyzed to isopropylate under the action of potassium carbonate, and then reduced and hydrolyzed to prepare 2-isopropyl valeric acid; the preparation reaction is as follows: R=benzyl, C1-C5 straight chain alkyl or C3-C5 branched alkyl; h + is selected from hydrochloric acid, sulfuric acid or phosphoric acid. The PTC is selected from: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide or tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide, tetramethylammonium iodide, cetyltrimethylammonium bromide, octadecyltrimethylammonium bromide, triethylbenzylammonium chloride, trimethylbenzylammonium chloride. The 2-isopropyl valeric acid is used for qualitative or quantitative analysis of impurities in the sodium valproate production process.

Description

Preparation method of 2-isopropyl valeric acid as valproic acid process impurity
Technical Field
The invention relates to a method for preparing 2-isopropyl valeric acid (C) as a technical impurity of valproic acid by adopting an atomic economy method.
Background
The impurities 2-methylpentanoic acid (L), 2-ethylpentanoic acid (B), 2-isopropylpentanoic acid (C), 2-methyl-2-ethylpentanoic acid (K) and dipropylpentanoic acid (D) in sodium valproate are reported in the european pharmacopoeia EP9.0 and british pharmacopoeia BP 2019:
Zhou Qiqun et al [ improved Process for synthesizing sodium valproate journal of Chinese medical industry 1993, 24 (8): 347-348 selecting methyl acetoacetate, and preparing sodium valproate by TEBA solid-liquid phase transfer catalytic alkylation, deacylation, hydrolysis and salification:
Wang Xueqin et al, 1999, J.En.1, J.pharmaceutical Industry, 1999, 30 (9): 389-390] selected methyl acetoacetate and potassium carbonate, and condensed with 1-bromopropane under TBAB catalysis to obtain methyl dipropylacetoacetate with a yield of 88%; in 2019 Lin Fanyou [ a process for synthesizing sodium valproate ], CN110563572A,2019-12-13] also adopts TBAB phase transfer catalysis to prepare sodium valproate.
Shanghai Qingping pharmaceutical Co., ltd. [ Wei Zhenghua, wei Jianguo, gu Yujin, jing Tao ] A process for the preparation of 2-R1 pentanoic acid, CN 202110336630.6, 2021.7.23; wei Zhenghua J pharmaceutical industry, synthesis of 2-isopropyl valeric acid, 2023,54 (05): 739-741] describes methyl cyanoacetate, methanol and 1-bromopropane, dropwise adding 30-40% sodium methoxide methanol solution at 45-60 ℃, after the reaction is completed, evaporating methanol by spin distillation to obtain crude product, and purifying to obtain methyl 2-cyanovalerate; the methyl 2-cyanovalerate is subjected to isopropylation, hydrolysis and decarboxylation to obtain 2-isopropylvaleric acid (C):
2-isopropyl valeric acid C is an impurity which is easy to produce in the preparation process of sodium valproate bulk drug, and plays a key role in detecting and controlling related substances in the production of sodium valproate bulk drug. The European pharmacopoeia EP9.0 and British pharmacopoeia BP2019 report the research and control application problems of impurity 2-isopropyl valeric acid (C) in sodium valproate. Therefore, the method has practical significance for the related research of the impurity C in the sodium valproate, and can be used for qualitative and quantitative analysis of the impurity in the sodium valproate production, so that the quality standard of the sodium valproate can be improved, and guidance is provided for safe medication.
Disclosure of Invention
The invention aims at providing an economic preparation method of 2-isopropyl valeric acid atom shown in a chemical structural formula C: the method is characterized in that propionyl acetate and 2-chloropropane are catalyzed to isopropylate under the action of potassium carbonate, and then reduced and hydrolyzed to prepare 2-isopropyl valeric acid; the preparation reaction is as follows:
R=benzyl, C1-C5 straight chain alkyl or C3-C5 branched alkyl; h + is selected from hydrochloric acid, sulfuric acid or phosphoric acid.
The invention aims to provide an economical preparation method of 2-isopropyl valeric acid atom, which comprises the following steps: the method is characterized in that propionyl ethyl acetate and 2-chloropropane are subjected to catalytic isopropylation under the action of alkali, and then reduced and hydrolyzed to prepare 2-isopropyl valeric acid; the preparation reaction is as follows:
The invention aims to provide an economical preparation method of 2-isopropyl valeric acid atom, which comprises the following steps: the method is characterized in that propionyl methyl acetate and 2-chloropropane are catalyzed to isopropylate under the action of alkali, and then reduced and hydrolyzed to prepare 2-isopropyl valeric acid; the preparation reaction is as follows:
PTC selection: r 4 NX or R 3R1 NX; wherein r=c1 to C5 straight chain alkyl; r 1＝PhCH2, C16 linear alkyl or C18 linear alkyl; wherein x=cl, br or I;
R 4 NX is selected from: TBAC, TBAB, TBAI, TPAC, TPAB, TPAI, TEAC, TEAB, TEAI, TMAC, TMAB or TMAI; TBAC, TBAB or TBAI are tetrabutylammonium chloride, tetrabutylammonium bromide or tetrabutylammonium iodide respectively; TPAC, TPAB or TPAI are tetrapropylammonium chloride, tetrapropylammonium bromide or tetrapropylammonium iodide, respectively; TEAC, TEAB or TEAI are tetraethylammonium chloride, tetraethylammonium bromide or tetraethylammonium iodide, respectively; TMAC, TMAB or TMAI is tetramethyl ammonium chloride, tetramethyl ammonium bromide or tetramethyl ammonium iodide, respectively.
R 3R1 NX is selected from: 1631. 1831, TEBA or TMBA;1631 is cetyl trimethylammonium bromide; 1831 is octadecyl trimethyl ammonium bromide; TEBA is triethylbenzyl ammonium chloride; TMBA is trimethylbenzyl ammonium chloride.
Solvent selection: THF, DMF, DMC, DMSO, acetonitrile, propionitrile, butyronitrile, 1, 4-dioxane, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether.
K 2CO3 is selected from: powder K 2CO3; powder K 2CO3 selection: 100 mesh K 2CO3, 150 mesh K 2CO3, 200 mesh K 2CO3, 250 mesh K 2CO3, 300 mesh K 2CO3 or 350 mesh K 2CO3.
Reaction temperature selection: 30-80 ℃; reaction time selection: 1.0 to 12 hours;
The catalytic amount is selected: propionyl acetate: ptc=1:0.005-0.10 molar ratio; propionyl acetate is selected from: one or two of methyl propionylacetate, ethyl propionylacetate, n-propyl propionylacetate, isopropyl propionylacetate, n-butyl propionylacetate, tert-butyl propionylacetate and benzyl propionylacetate.
The second aspect of the object of the present invention is to provide a process for reducing 2-isopropyl-3-oxopentanoate to 2-isopropyl pentanoate by selecting CLEMMENESE reaction, CLEMMENESE reaction as follows:
2-isopropyl-3-oxo valerate is reduced by Zn-Hg in 5% HCl and toluene reflux to obtain 2-isopropyl valerate.
The third aspect of the invention aims to provide the application of the 2-isopropyl valeric acid in qualitative or quantitative analysis of impurities in the sodium valproate production process.
Compared with the prior art, the invention has the following advantages:
1. In the invention, a catalytic isopropylation method of propionyl acetate and 2-chloropropane is adopted: the 2-chloropropane has rich sources and low cost.
2. The process of the invention is a method for preparing 2-isopropyl valeric acid in atom economy, and is green and environment-friendly; the process does not break C-C bond, carbon dioxide is not discharged to the air in the process, and the utilization rate of carbon atoms is high.
Drawings
Figure 1 2-isopropyl valeric acid gas phase chromatogram
FIG. 2 valproic acid gas phase chromatogram
FIG. 3 gas chromatogram of valproic acid mixed with 2-isopropylvaleric acid
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1
Preparation of ethyl 2-isopropyl-3-oxopentanoate
0.20Mol of ethyl propionylacetate, 10mmol of tetraethylammonium bromide (TEAB), 60.8g (0.44 mol) of K 2CO3 (200 meshes), 80ml of DMF and 0.30mol of 2-chloropropane, stirring and reacting for 4.0h at 60 ℃, cooling and filtering solid inorganic salt after the reaction; 300mL of water is added to dissolve solid inorganic salt, standing is carried out, layering is carried out, the lower layer is water phase, the upper layer liquid is combined with filtrate (filtrate for filtering inorganic salt), DMF is recovered under reduced pressure under 16mmHg, residual liquid (filtrate 1) is obtained, petroleum ether (60 mL multiplied by 3) is used for extraction after being combined with water phase, the organic phase is washed with water for 60mL multiplied by 3, anhydrous sodium sulfate is dried, suction filtration is carried out, petroleum ether is recovered by rotary evaporation, 25.3g of 2-isopropyl-3-oxo valerate is rectified, and the yield is 67.9%.
Example 2
Preparation of ethyl 2-isopropyl valerate
0.20Mol of ethyl 2-isopropyl-3-oxovalerate was refluxed in 5% HCl and toluene, and 14.4g of ethyl 2-isopropyl valerate was obtained by Zn-Hg reduction, and the yield was 41.8%.
Example 3
Preparation of 2-isopropyl valeric acid (C)
Dropwise adding a potassium hydroxide aqueous solution (KOH: 60g, H 2 O:100 ml) into 0.20mol of ethyl 2-isopropyl valerate, heating to 85 ℃, stirring and hydrolyzing for 5.0h; cooling and separating the water layer; adding 180ml of water into the organic phase, standing for layering, separating oil phase, adding hydrochloric acid into the water phase for regulating pH to 1, standing for layering, drying the oil phase, and rectifying under reduced pressure to obtain 26.1g of 2-isopropyl valeric acid C, with yield 90.5％.1H NMR(DMSO-d6,400MHz)δ：11.78(brs,1H,CO2H),2.16～2.11(m,1H,CH),1.92～1.86(m,1H,CH),1.64～1.45(m,2H,CH2),1.42～1.25(m,2H,CH2),0.97(d,J＝7.2Hz,6H,CH3×2),0.91(t,J＝7.2Hz,3H,CH3).
Example 4
Preparation of 2-isopropyl valeric acid (C)
Methyl propionylacetate was chosen as starting material and 2-isopropylpentanoic acid C was prepared as described in examples 1 to 3 using tetrabutylammonium bromide (TBAB) as catalyst.
Example 5 (control)
Preparation of 2-isopropyl valeric acid (C)
According to Shanghai Qingping pharmaceutical Co Ltd [ CN 202110336630.6; the synthesis of 2-isopropylvaleric acid, 2023,54 (05): 739-741] in the journal of the Chinese medical industry:
(1) Preparation of methyl 2-cyanovalerate
Methyl 2-cyanoacetate (720.00 g,7.27 mol), methanol (1140.00 g) and n-bromopropane (714.88 g,5.81 mol) were added to a reaction flask, heated to 50℃and a 30% sodium methoxide methanol solution (784.80 g,4.36 mol) was added dropwise with stirring, the temperature was controlled at 50 to 60℃during the period, bi Huiliu h was dropped, the methanol was distilled off under normal pressure, isopropyl acetate (800 mL) was added to the remaining solid-liquid mixture (about 1268.00 g), slurried, filtered, and desalted, and the obtained isopropyl acetate phase was washed with a 5% sodium hydroxide solution (500 mL. Times.6), washed with 1% sulfuric acid (500 mL) and water (500 mL) in this order, concentrated to dryness (360.00 g), distilled off with a rectifying column (2.5 cm. Times.1.2 m. Times.3 mm), and a fraction of bp 60 ℃/140Pa was collected to obtain methyl 2-cyanovalerate (173.87 g, 17%) as a colorless transparent liquid, with a purity of 98.5%.
(2) Preparation of methyl 2-cyano-2-isopropyl valerate
Methyl 2-cyanovalerate (40.00 g,0.28 mol), methanol (60.00 g) and 2-iodopropane (50.60 g,0.30 mol) are added into a reaction bottle, a 30% sodium methoxide methanol solution (56.00 g,0.31 mol) is dropwise added at the temperature of 40-50 ℃, the temperature is raised to reflux reaction for 3 hours after the dropwise addition, the reaction liquid is concentrated to dryness under reduced pressure, isopropyl acetate (150 mL) and water (100 mL) are added into the residues, the organic phase is concentrated under reduced pressure (0.1 MPa) at 50 ℃, the organic phase is continuously pumped under reduced pressure at 45 ℃ for 0.5h by an oil pump, and then 69 ℃/40Pa fractions are collected by reduced pressure distillation, so that pale yellow liquid methyl 2-cyano-2-isopropyl valerate (34.38 g, 67%) is directly put into the next reaction.
(3) Preparation of 2-isopropyl valeric acid (C)
Water (32.00 g) was added to the reaction flask, concentrated sulfuric acid (33.00 g,0.33 mol) and methyl 2-cyano-2-isopropyl valerate (25.00 g,0.14 mol) obtained in (2) were slowly added, the mixture was stirred and heated to reflux, water was slowly separated until the internal temperature reached 150℃and the reaction was continued for 20 hours. After cooling, water (20 mL) was added to the reaction mixture, the phases were separated, the organic phase was washed with water (15 mL. Times.3), 15% sodium hydroxide solution (31.00 g) was added, and the mixture was stirred at 60℃for 5 hours. Cooling to room temperature, adding water (30.00 g), extracting with dichloromethane (10 mL. Times.3), adding 98% sulfuric acid (7.82 g) into the aqueous phase to adjust the pH to 1, separating phases, extracting an organic phase with water (10 mL. Times.3), concentrating under reduced pressure at 60 ℃ by an oil pump until no distillate exists, and obtaining light yellow liquid 2-isopropyl valeric acid (C, 7.00g, yield 35%), purity 98%, bp 84 ℃/30Pa.
Example 6
Application of 2-isopropyl valeric acid
2-Isopropyl valeric acid is used for qualitative analysis of impurities in sodium valproate production process. The prepared valproic acid was detected by gas chromatography using a gas chromatograph (Agilent 8890).
The chromatographic detection conditions were as follows: chromatographic column: DB-FFAP (0.32 mm. Times.60 m,0.5 μm); carrier gas: nitrogen gas; a detector: FID; flow rate: 2ml/min; sample injection volume: 2 μl; sample inlet temperature: 220 ℃; column temperature: 100 ℃; heating program: the initial temperature is 100 ℃, kept for 5min, then heated to 140 ℃ at the speed of 4 ℃/min, kept for 5min, and then heated to 200 ℃ at the speed of 4 ℃/min, and kept for 15min. Run time: 50min; detector temperature: 220 ℃; sample injection mode: and (5) directly sampling.
Taking 2 μl of each of the diluent, the reference solution and the sample solution, injecting into a gas chromatograph, and recording the chromatogram.
The gas chromatogram detection result of 2-isopropyl valeric acid (C) is shown in figure 1, and the retention time is 29.078min.
The detection result of the gas chromatogram of valproic acid is shown in figure 2; wherein peak retention time No. 3 is 29.088min, rrt=0.96, peak area 0.029%: 2-isopropylvaleric acid; peak retention time No. 4 30.246min, rrt=1.00: valproic acid.
The detection result of the mixed gas chromatogram of valproic acid and 2-isopropyl valeric acid is shown in figure 3; wherein peak retention time No. 3 is 29.093min, rrt=0.96, peak area rises to 1.105%: 2-isopropylvaleric acid; peak retention time No. 4 30.240min, rrt=1.00: valproic acid.
Conclusion: peak No. 3 (rrt=0.96) in fig. 2 and fig. 3 is 2-isopropylvaleric acid (C); one major impurity in the valproic acid product is 2-isopropyl valeric acid, which has the structural formula:
In this specification, the invention has been described with reference to specific embodiments thereof. It will be apparent that various modifications and variations can be made without departing from the spirit and scope of the invention. The description is thus to be regarded as illustrative instead of limiting.

Claims (6)

1. The preparation method of the 2-isopropyl valeric acid shown in the chemical structural formula C is characterized in that propionyl acetate and 2-chloropropane are subjected to catalytic isopropylation under the action of potassium carbonate, and then are subjected to reduction and hydrolysis to prepare the 2-isopropyl valeric acid; the preparation reaction is as follows:
R=c1 to C5 straight chain alkyl or C3 to C5 branched alkyl; h + is selected from hydrochloric acid, sulfuric acid or phosphoric acid;
The alkylated PTC is selected from: tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrapropylammonium chloride, tetrapropylammonium bromide, tetrapropylammonium iodide, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, tetramethylammonium chloride, tetramethylammonium bromide or tetramethylammonium iodide;
And (3) selecting an alkylation solvent: DMF or DMC;
Alkylation K 2CO3 selection: 100 mesh K 2CO3, 150 mesh K 2CO3, 200 mesh K 2CO3, 250 mesh K 2CO3, 300 mesh K 2CO3 or 350 mesh K 2CO3;
the alkylation reaction temperature is selected: the alkylation reaction time is 1.0h to 12.0h at the temperature of 30 ℃ to 80 ℃.
2. The preparation method of the 2-isopropyl valeric acid shown in the chemical structural formula C is characterized in that propionyl ethyl acetate and 2-chloropropane are subjected to catalytic isopropylation under the action of potassium carbonate, and then are subjected to reduction and hydrolysis to prepare the 2-isopropyl valeric acid; the preparation reaction is as follows:
The alkylation PTC, solvent, K 2CO3, alkylation reaction temperature and alkylation reaction time are defined in claim 1.
3. The preparation method of the 2-isopropyl valeric acid shown in the chemical structural formula C is characterized in that propionyl methyl acetate and 2-chloropropane are subjected to catalytic isopropylation under the action of potassium carbonate, and then are subjected to reduction and hydrolysis to prepare the 2-isopropyl valeric acid; the preparation reaction is as follows:
The alkylation PTC, solvent, K 2CO3, alkylation reaction temperature and alkylation reaction time are defined in claim 1.
4. A process for the preparation of 2-isopropylvaleric acid according to any one of claims 1 to 3, wherein the dosage is selected from: propionyl acetate 2-chloropropane=1:1.2-1.6 molar ratio; PTC usage amount selection: propionyl acetate: ptc=1:0.005-0.10 molar ratio.
5. The process for producing 2-isopropylvaleric acid according to claim 1, wherein propionyl acetate is selected from the group consisting of: methyl propionylacetate, ethyl propionylacetate, n-propyl propionylacetate, isopropyl propionylacetate, n-butyl propionylacetate or tert-butyl propionylacetate.
6. The process for preparing 2-isopropylvaleric acid according to claim 1, wherein the reduction of 2-isopropyl-3-oxovalerate to 2-isopropylvalerate, CLEMMENESE, is carried out as follows:
Refluxing 2-isopropyl-3-oxo valerate in 5% HCl and toluene, and reducing by Zn-Hg to obtain 2-isopropyl valerate; r is as defined in claim 1.
CN202310841425.4A 2023-07-10 2023-07-10 Preparation method of 2-isopropyl valeric acid as valproic acid process impurity Active CN116947600B (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114763319A (en) * 2022-05-16 2022-07-19 湖南大学 Method for co-producing valproamide and sodium valproate
CN116023232A (en) * 2023-01-03 2023-04-28 湖南省湘中制药有限公司 Preparation method of propyl malonic acid and homologs thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114763319A (en) * 2022-05-16 2022-07-19 湖南大学 Method for co-producing valproamide and sodium valproate
CN116023232A (en) * 2023-01-03 2023-04-28 湖南省湘中制药有限公司 Preparation method of propyl malonic acid and homologs thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Late-Stage β‑C(sp3)−H Deuteration of Carboxylic Acids;Alexander Uttry，等;J. Am. Chem. Soc.;20210719;第143卷;全文 *
欧洲药典10.0.2017,第3849-3850页. *

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