CN114369089A - Preparation method of impurities of horizon drugs - Google Patents
Preparation method of impurities of horizon drugs Download PDFInfo
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- CN114369089A CN114369089A CN202210140977.8A CN202210140977A CN114369089A CN 114369089 A CN114369089 A CN 114369089A CN 202210140977 A CN202210140977 A CN 202210140977A CN 114369089 A CN114369089 A CN 114369089A
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- 239000003814 drug Substances 0.000 title claims abstract description 61
- 239000012535 impurity Substances 0.000 title claims abstract description 61
- 229940079593 drug Drugs 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 239000012044 organic layer Substances 0.000 claims abstract description 17
- 238000003756 stirring Methods 0.000 claims abstract description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000012043 crude product Substances 0.000 claims abstract description 11
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000002156 mixing Methods 0.000 claims abstract description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005406 washing Methods 0.000 claims abstract description 9
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000003054 catalyst Substances 0.000 claims abstract description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 7
- 238000001035 drying Methods 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 5
- 238000001914 filtration Methods 0.000 claims abstract description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 33
- RWNNRGBCWXOVAC-UHFFFAOYSA-N 1,4-bis[bis(aziridin-1-yl)phosphoryl]piperazine Chemical compound C1CN1P(N1CCN(CC1)P(=O)(N1CC1)N1CC1)(=O)N1CC1 RWNNRGBCWXOVAC-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 230000010933 acylation Effects 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 150000003431 steroids Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 23
- 239000000203 mixture Substances 0.000 description 15
- JPXPPUOCSLMCHK-UHFFFAOYSA-N 5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid Chemical compound COC(=O)C1=C(C)NC(C)=C(C(O)=O)C1C1=CC=CC([N+]([O-])=O)=C1 JPXPPUOCSLMCHK-UHFFFAOYSA-N 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- XILIYVSXLSWUAI-UHFFFAOYSA-N 2-(diethylamino)ethyl n'-phenylcarbamimidothioate;dihydrobromide Chemical compound Br.Br.CCN(CC)CCSC(N)=NC1=CC=CC=C1 XILIYVSXLSWUAI-UHFFFAOYSA-N 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 238000005100 correlation spectroscopy Methods 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 238000003919 heteronuclear multiple bond coherence Methods 0.000 description 1
- 238000001052 heteronuclear multiple bond coherence spectrum Methods 0.000 description 1
- 238000005570 heteronuclear single quantum coherence Methods 0.000 description 1
- 238000000990 heteronuclear single quantum coherence spectrum Methods 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/14—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing 9-azabicyclo [3.3.1] nonane ring systems, e.g. granatane, 2-aza-adamantane; Cyclic acetals thereof
Abstract
The invention provides a preparation method of a horizontal medicine impurity, which comprises the following steps: firstly, uniformly mixing a ground-plane mother nucleus, a reaction solvent and a catalyst, adding an acylating reagent, and stirring for reaction to obtain a first reaction solution; and then adding water into the first reaction solution, keeping the temperature for reaction, adding alkali liquor for washing, taking an organic layer, concentrating and drying to obtain a crude product of the impurities of the flat class, stirring and washing the crude product of the impurities in ethyl acetate, and filtering and drying to obtain the impurities of the flat class drug. The preparation method is simple, the purity of the obtained impurities reaches 99.6%, and the method has a good application prospect in the production of the flat drugs.
Description
Technical Field
The invention relates to the technical field of medical compounds, in particular to a preparation method of impurities of a horizontal class drug.
Background
The medicine of the present invention is one kind of dihydropyridine calcium antagonist for preventing and treating coronary heart disease and angina pectoris, especially coronary heart disease and angina pectoris caused by coronary spasm, and is also suitable for treating various kinds of hypertension and intractable and severe hypertension. The structure of the horizontal medicine contains similar structures, and the structural main body is shown as the following structural formula:
at present, the synthetic routes of the drugs are generally selected
The compound is used as a key starting material or an intermediate, and then is condensed with different side chains to obtain different flat drugs, the synthesis mode can generate an intermolecular flat impurity, the research on the impurity is an important content in drug research, and the impurity has a great relevance to the safety and the effectiveness of medicines, so that the preparation method of the flat impurity needs to be provided.
Disclosure of Invention
In view of the above, the invention provides a preparation method of impurities of a horizontal drug.
The technical scheme of the invention is realized in such a way that the invention provides a preparation method of a horizontal drug impurity, which comprises the following steps:
step one, uniformly mixing a flat parent nucleus, a reaction solvent and a catalyst, adding an acylation reagent, and stirring for reaction to obtain a first reaction solution;
and step two, adding water into the first reaction solution, preserving the heat at 20-30 ℃ for reaction for 2-4h, then adding alkali liquor for washing, taking an organic layer, concentrating and drying to obtain a crude product of the impurities of the horizontal drugs.
On the basis of the technical scheme, preferably, the structural formula of the impurities of the horizontal type drugs is as follows:
the structural formula of the horizontal class mother nucleus is as follows:
on the basis of the technical scheme, preferably, the reaction solvent is one of dichloromethane and chloroform, and the mass ratio of the binary nucleus to the reaction solvent is 1 (3-10).
On the basis of the above technical scheme, preferably, the acylating reagent is thionyl chloride or phosphorus pentachloride, and the molar ratio of the flat parent nucleus to the acylating reagent is 1: (1-2).
On the basis of the technical scheme, preferably, the catalyst is N, N-dimethylformamide, and the molar ratio of the binary parent nucleus to the catalyst is 1: (2-8).
Still further preferably, the weight ratio of the ground parent nucleus to water is 1: (0.1-0.5).
On the basis of the above technical scheme, the temperature for adding the acylating agent is preferably 0-10 ℃.
On the basis of the technical scheme, the stirring reaction temperature in the step one is preferably 0-10 ℃, and the reaction time is 1-3 h.
On the basis of the above technical scheme, preferably, the alkali liquor in the step two is a sodium hydroxide solution, and the number of times of washing with the alkali liquor is 1-3 times.
On the basis of the technical scheme, the method preferably further comprises a third step of mixing the crude product of the impurities of the dipine drugs with a refined solvent, uniformly stirring, filtering, and drying to obtain the impurities of the dipine drugs, wherein the refined solvent is ethyl acetate.
On the basis of the technical scheme, preferably, the impurities of the horizontal class medicine are used as a reference substance for quality research of the horizontal class medicine.
Compared with the prior art, the preparation method of the impurities of the horizontal class medicine has the following beneficial effects:
(1) the invention provides a preparation method of impurities of a horizontal class drug, which has simple preparation process, mild conditions and higher yield and purity of the obtained product;
(2) the impurities of the horizontal class medicine prepared by the preparation method can be used for medicine analysis, thereby being beneficial to controlling the content of the impurities in the medicine and improving the quality level of the medicine.
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, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 shows impurities of the drug of the present invention1HNMR spectrogram;
FIG. 2 shows impurities of the drug of the present invention13CNMR spectrogram;
FIG. 3 is DEPT spectrogram of impurities of the dipine drug prepared by the present invention;
FIG. 4 is a COSY spectrogram of impurities of the dipine drug prepared by the invention;
FIG. 5 is an HSQC spectrum of the impurities of the dipine drug prepared by the present invention;
FIG. 6 is a HMBC spectrum of a dipine drug impurity prepared in accordance with the present invention;
FIG. 7 is a high resolution mass spectrum of impurities of the dipine drug prepared by the present invention;
FIG. 8 is a high resolution mass spectrum of impurities of the present invention prepared from the drug of the present invention;
FIG. 9 is an infrared spectrogram of impurities of the dipine drug prepared by the present invention;
FIG. 10 is a possible structure analysis diagram of m/z 560, m/z545, m/z430, m/z 289 and the like in MS of the impurities of the horizontal class drug prepared by the invention.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without any inventive step based on the embodiments of the present invention, are within the scope of the present invention.
The structural formula of the raw material, namely the binary parent nucleus, adopted in the following examples is as follows:
example 1
The binary parent nucleus is called as the binary parent nucleus: 332g of 5- (methoxycarbonyl) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic acid, 1000g of dichloromethane and 146g of N, N-dimethylformamide are uniformly mixed, the temperature is kept between 0 and 10 ℃, 119g of thionyl chloride is added, and after the addition is finished, the temperature is kept between 0 and 10 ℃, and the mixture is kept for heat preservation and stirring reaction for 1 hour to obtain a first reaction solution.
And adding 33.2g of water into the first reaction solution, keeping the temperature of the mixture at 20 ℃ for reaction for 2 hours, then adding 100ml of 0.1N sodium hydroxide aqueous solution, mixing and stirring the mixture evenly, standing the mixture for layering, taking an organic layer, and concentrating the organic layer under reduced pressure until the mixture is dried to obtain 251g of crude product of the impurities of the dipine drugs, wherein the calculated yield is 87.2%.
Example 2
The binary parent nucleus is called as the binary parent nucleus: 332g of 5- (methoxycarbonyl) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic acid, 1328g of dichloromethane and 365g of N, N-dimethylformamide are uniformly mixed, the temperature is kept at 0-10 ℃, 238g of thionyl chloride is added, and after the addition is finished, the temperature is kept at 0-10 ℃, and the reaction is kept for 2 hours under the condition of heat preservation and stirring to obtain a first reaction solution.
And adding 99.6g of water into the first reaction solution, keeping the temperature of the first reaction solution at 25 ℃ for reaction for 3 hours, then adding 100ml of 0.1N sodium hydroxide aqueous solution, mixing and stirring the mixture uniformly, standing the mixture for layering, repeating the operation of washing and layering the sodium hydroxide solution for 2 times, taking an organic layer, and concentrating the organic layer under reduced pressure until the organic layer is dried to obtain 252g of crude products of the impurities of the flat drugs, wherein the calculated yield is 87.6%.
Example 3
The binary parent nucleus is called as the binary parent nucleus: 332g of 5- (methoxycarbonyl) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic acid, 1660g of dichloromethane and 584g of N, N-dimethylformamide are uniformly mixed, then 208g of phosphorus pentachloride is added at the temperature of 0-10 ℃, and after the addition is finished, the temperature is kept at the temperature of 0-10 ℃ and the mixture is stirred and reacted for 2 hours to obtain a first reaction solution.
And adding 166g of water into the first reaction solution, keeping the temperature of the first reaction solution at 30 ℃ for reaction for 4 hours, then adding 100ml of 0.1N sodium hydroxide aqueous solution, mixing and stirring the mixture uniformly, standing the mixture for layering, repeating the above sodium hydroxide solution cleaning and layering operation for 2 times, taking an organic layer, and concentrating the organic layer under reduced pressure until the organic layer is dried to obtain 255g of crude products of the impurities of the flat drugs, wherein the calculated yield is 88.6%.
Example 4
Weighing a horizontal parent nucleus: 332g of 5- (methoxycarbonyl) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic acid, 2000g of dichloromethane and 584g of N, N-dimethylformamide are uniformly mixed, then the temperature is kept between 0 and 10 ℃, 416g of phosphorus pentachloride is added, and after the addition is finished, the temperature is kept between 0 and 10 ℃, and the mixture is stirred and reacted for 2 hours to obtain a first reaction solution.
And adding 166g of water into the first reaction solution, keeping the temperature of the first reaction solution at 30 ℃ for reaction for 4 hours, then adding 100ml of 0.1N sodium hydroxide aqueous solution, mixing and stirring the mixture uniformly, standing the mixture for layering, repeating the washing and layering operation of the sodium hydroxide solution for 3 times, taking an organic layer, and concentrating the organic layer under reduced pressure until the organic layer is dried to obtain 253.1g of crude drug impurities of the flat class, wherein the calculated yield is 88.1%.
Example 5
Weighing a horizontal parent nucleus: 332g of 5- (methoxycarbonyl) -2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3-carboxylic acid, 3320g of dichloromethane and 365g of N, N-dimethylformamide are uniformly mixed, the temperature is kept at 0-10 ℃, 238g of thionyl chloride is added, and after the addition is finished, the temperature is kept at 0-10 ℃, and the reaction is kept for 2 hours under the condition of heat preservation and stirring to obtain a first reaction solution.
And adding 99.6g of water into the first reaction solution, keeping the temperature of the first reaction solution at 25 ℃ for reaction for 3 hours, then adding 100ml of 0.1N sodium hydroxide aqueous solution, mixing and stirring the mixture evenly, standing the mixture for layering, repeating the operation of washing and layering the sodium hydroxide solution for 2 times, taking an organic layer, and concentrating the organic layer under reduced pressure until the organic layer is dried to obtain the crude product of the impurities of the flat drugs.
Mixing and stirring the crude product of the impurities of the dipine drugs and 2000g of ethyl acetate, and then filtering and drying to obtain 220.8g of impurities of the dipine drugs, wherein the yield is 76.7%.
The impurities of the dipine drugs prepared in example 5 were respectively processed1HNMR、13The results of CNMR, HSQC, HMBC, COSY and DEPT tests are shown in FIGS. 1-9, and are as follows:
the impurity has a molecular weight of 577.22829([ M + H ] when measured by high-resolution mass spectrometry+]) And theoretical molecular mass of 577.22929([ M + H ]+]) ATherefore, the molecular formula is assumed to be C30H32O8N4, which is consistent with the theoretical derivation.
There are m/z 560, m/z545, m/z430, m/z 289, etc. in the MS, which may be attributed as shown in FIG. 10.
Hydrogen spectrum of the impurity1The results of HNMR measurements are given in the following table:
carbon spectrum of the impurity13The results of the CNMR measurements are given in the following table:
the structure of the impurity is presumed to be as follows:
the preparation method of the impurities of the dipine drugs provided by the invention is simple, the obtained product has high yield, the detection purity reaches 99.6%, and the impurities of the dipine drugs have good application prospects in the production of the dipine drugs.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A preparation method of a horizontal medicine impurity is characterized by comprising the following steps:
step one, uniformly mixing a flat parent nucleus, a reaction solvent and a catalyst, adding an acylation reagent, and stirring for reaction to obtain a first reaction solution;
and step two, adding water into the first reaction solution, preserving the heat at 20-30 ℃ for reaction for 2-4h, then adding alkali liquor for washing, taking an organic layer, concentrating and drying to obtain a crude product of the impurities of the horizontal drugs.
2. The method for preparing the impurities of the dipine drugs according to claim 1, wherein the structural formula of the impurities of the dipine drugs is:
the structural formula of the horizontal class mother nucleus is as follows:
3. the method for preparing impurities of the dipine drugs according to claim 1, wherein the reaction solvent is one of dichloromethane and chloroform, and the mass ratio of the dipine parent nucleus to the reaction solvent is 1 (3-10).
4. The method for preparing impurities of a dipine drug according to claim 1, wherein the acylating agent is thionyl chloride or phosphorus pentachloride, and the molar ratio of the dipine parent nucleus to the acylating agent is 1: (1-2).
5. The method for preparing the impurities of the dipine drugs according to claim 1, wherein the catalyst is N, N-dimethylformamide, and the molar ratio of the dipine parent nucleus to the catalyst is 1: (2-8).
6. The method for preparing the impurities of the dipine drugs according to claim 1, wherein the weight ratio of the dipine parent nucleus to water is 1: (0.1-0.5).
7. The method for preparing the impurities of the steroid drug as claimed in claim 1, wherein the temperature of adding the acylating agent is 0-10 ℃.
8. The method for preparing the impurities of the dipine drugs according to claim 1, wherein the stirring reaction in the first step is performed at a temperature of 0 to 10 ℃ for a reaction time of 1 to 3 hours.
9. The method for preparing impurities of the dipine drugs according to claim 1, wherein the alkali solution in the second step is sodium hydroxide solution, and the number of washing times of the alkali solution is 1 to 3.
10. The method for preparing impurities of the dipine drugs according to claim 1, further comprising a third step of mixing the crude products of the impurities of the dipine drugs with a refined solvent, stirring uniformly, filtering, and drying to obtain the impurities of the dipine drugs, wherein the refined solvent is ethyl acetate.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744345A (en) * | 2013-12-26 | 2015-07-01 | 李磊 | Preparation method of lercanidipine |
| CN109956943A (en) * | 2019-04-18 | 2019-07-02 | 合肥合源药业有限公司 | Decarboxylation condensation impurity and its preparation, control method in a kind of Dihydropyridines drugs |
| CN111116553A (en) * | 2019-12-10 | 2020-05-08 | 北京鑫开元医药科技有限公司 | Preparation method of dihydropyridone derivatives |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104744345A (en) * | 2013-12-26 | 2015-07-01 | 李磊 | Preparation method of lercanidipine |
| CN109956943A (en) * | 2019-04-18 | 2019-07-02 | 合肥合源药业有限公司 | Decarboxylation condensation impurity and its preparation, control method in a kind of Dihydropyridines drugs |
| CN111116553A (en) * | 2019-12-10 | 2020-05-08 | 北京鑫开元医药科技有限公司 | Preparation method of dihydropyridone derivatives |
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Application publication date: 20220419 |