CN109293581B - Method for preparing rilpivirine hydrochloride isomer Z and impurity X and application of impurity X as pesticide in agriculture - Google Patents
Method for preparing rilpivirine hydrochloride isomer Z and impurity X and application of impurity X as pesticide in agriculture Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical chemistry synthesis, and relates to a method for preparing rilpivirine hydrochloride isomer Z and impurity X and application of impurity X as a pesticide in agriculture. The isomer Z has a structure represented by formula (I):
the impurity X has a structure shown in (II):
the rilpivirine hydrochloride isomer Z or the impurity X or the combination thereof is obtained by separating from reaction liquid during rilpivirine preparation. The invention improves the impurity spectrum of rilpivirine hydrochloride and has extremely important significance for realizing the quality control of rilpivirine hydrochloride and preparations thereof.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a method for preparing rilpivirine hydrochloride isomer Z and impurity X and application of impurity X as a pesticide in agriculture.
Background
Rilpivirine hydrochloride (Rilpivirine hydrochloride) is a novel non-nucleoside reverse transcriptase inhibitor developed by Tibotec company in America, is used for treating AIDS, has a trade name of Edurant, is approved by FDA in the United states for marketing in 2011, 5 months and 20 days, and has the characteristics of easy synthesis, strong antiviral activity, high oral bioavailability, good safety and the like. The compound is a diaryl pyrimidine medicine, the Chinese cultural name is 4- [ [4- [ [4- [ (1E) -2-cyanoethyl ] -2, 6-dimethylphenyl ] amino ] -2-pyrimidinyl ] amino ] -benzonitrile, and the structural formula is as follows:
ripivirine hydrochloride and other non-nucleoside reverse transcriptase inhibitors are used together clinically, and the composition is mainly used for HIV-1 adult infected persons without HIV treatment history. Rilpivirine hydrochloride does not cure HIV infection and patients must adhere to continuous HIV therapy to control HIV infection and reduce the incidence of HIV-related diseases. Rilpivirine is more effective against a broad spectrum of NNRTI-resistant viruses (including viruses resistant to efavirenz) than efavirenz.
At present, no report is made in the published literature about the impurities of rilpivirine hydrochloride. Rilpivirine impurity A, rilpivirine impurity B, rilpivirine impurity C, rilpivirine impurity D, rilpivirine impurity E, rilpivirine impurity F, rilpivirine impurity G, rilpivirine impurity H, rilpivirine impurity I, rilpivirine impurity J, rilpivirine impurity L, rilpivirine impurity M, rilpivirine impurity N, rilpivirine impurity O and rilpivirine impurity P are sold in the market, but the chemical names or structural formulas of the impurities are not disclosed.
The applicant has associated with Toronto Research Chemicals, Canada, TRC and bought the rilpivirine hydrochloride isomer Z as an impurity, which is said to be a mixture in which the Z-configuration is only about 50%, i.e., no purer Z isomer is currently available on the market and no reports are made thereon.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for preparing rilpivirine hydrochloride isomer Z and impurity X and application of impurity X as pesticide in agriculture.
The technical scheme of the invention is as follows:
the invention aims to provide a rilpivirine hydrochloride isomer Z and an impurity X, which have structures shown in a formula (I) and a formula (II):
another object of the present invention is to provide a method for preparing rilpivirine hydrochloride isomer Z and impurity X, specifically comprising the following steps:
in the preparation of rilpivirine, applicants have found that even when all-trans E-3- (4-amino-3, 5-dimethylphenyl) -2-acrylonitrile hydrochloride is used, about 15% of rilpivirine Z-isomer and about 0.5% of impurity X are always produced during the reaction.
Through a large number of experimental researches, in order to generate Z-configuration isomer impurities and impurities X as much as possible in the reaction for preparing rilpivirine, in the preparation process of rilpivirine, amino hydrogen of the compound shown in the formula I can be activated by an electron-withdrawing group, and meanwhile, by utilizing the property of easy leaving, Z-isomer impurities (about 50%) and impurities X (about 5%) can be generated in a large amount under the catalysis of high temperature and alkali in a polar aprotic solvent;
filtering alkali and rilpivirine in the reaction, and leaving Z-isomer and impurity X in the filtrate;
concentrating the filtrate to dryness, reacting with acid in alcohol to obtain salt, and filtering to remove E-isomer mixed in the filtrate, wherein the filtrate only contains pure Z-isomer and impurity X;
concentrating the filtrate, separating Z-isomer and impurity X salt by alcohol recrystallization or column chromatography or preparative liquid phase separation, and dissociating with alkali to obtain Z-isomer and impurity X. Since Z and X are in the form of bases, not salts, this step is not necessary if they are in the form of salts.
Namely, the rilpivirine hydrochloride isomer Z and the impurity X are separated from the reaction liquid for preparing rilpivirine.
The synthetic route of rilpivirine is as follows:
the synthesis of intermediate IV is described in WO2004016581A1, example A3.
Further preferably, the catalyst base in the preparation of rilpivirine is potassium carbonate, sodium carbonate, potassium tert-butoxide, N-diisopropylethylamine.
Further preferably, the reaction temperature for preparing rilpivirine is 60-150 ℃.
Further preferably, the reaction solvent for preparing rilpivirine is ethanol, isopropanol, acetonitrile, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, 2-methyltetrahydrofuran, or ethylene glycol dimethyl ether.
Further preferably, the reaction solution of rilpivirine is subjected to salt formation with an acid after removing the base and rilpivirine.
Further preferably, the acid includes hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, oxalic acid, fumaric acid, maleic acid.
Further preferably, the method for preparing the rilpivirine hydrochloride isomer Z and the impurity X comprises the separation and purification of the isomer Z and the impurity X, wherein the purification method is selected from any one or combination of recrystallization, column chromatography and preparative liquid phase separation refining.
Further preferably, the recrystallization solvent of the present invention is an alcohol including one of methanol, ethanol, isopropanol, n-butanol or a combination thereof.
Further preferably, in the method for preparing rilpivirine hydrochloride isomer Z and impurity X, the refining conditions of column chromatography and preparative liquid phase separation are that an eluent or a mobile phase is any one or combination of methanol-water, acetonitrile-water and methanol-acetonitrile-water, isocratic or gradient elution is carried out, product fractions are collected and evaporated to dryness or freeze drying is carried out, thus obtaining the rilpivirine hydrochloride isomer Z and impurity X.
The invention has the following beneficial effects:
1. the rilpivirine hydrochloride isomer Z and the impurity X can be used as a standard substance or a reference substance. A large number of researches show that the rilpivirine hydrochloride impurity X is a newly found compound, and the purity of HPLC (high performance liquid chromatography) can reach more than 98 percent through the preparation of the rilpivirine hydrochloride impurity X; the isomer impurity Z prepared by the method has the purity of over 95 percent by HPLC, can be used as a reference substance or a standard substance of rilpivirine hydrochloride impurities, and provides a basis for quality research of rilpivirine hydrochloride.
2. The impurity X can also be used as a pesticide in agriculture.
Drawings
FIG. 1 HPLC plot of the purchased Z-isomer impurity (left: Z-isomer, right: E-isomer);
FIG. 2 HPLC plot of Z-isomer impurity prepared according to the present invention (left: Z-isomer, right: E-isomer);
FIG. 3 is an HPLC plot of impurity X prepared by the present invention;
FIG. 4 of Z-isomer impurities prepared according to the invention1H-NMR chart;
FIG. 5 the present inventionOf prepared impurity X1H-NMR chart;
FIG. 6 is a mass spectrum of impurity X prepared according to the present invention;
FIG. 7 is a mass spectrum of Z-isomer impurities prepared in accordance with the present invention;
FIG. 8 of the E-isomer (rilpivirine)1H-NMR chart.
Detailed Description
The invention is further illustrated by the following examples, but the scope of the invention as claimed is not limited to the scope of the examples.
EXAMPLE 1 preparation of impurity X and isomer Z
(1) The synthesis method of the compound shown in the formula III (R is trifluoroacetyl) is as follows:
adding 117.2 g of the compound shown in the formula V into 18ml of acetonitrile, adding 10.1g (1eq) of triethylamine, cooling to 0 ℃, dropwise adding 21g (1eq) of trifluoroacetic anhydride, controlling the temperature in the dropwise adding process to be less than 30 ℃, after the dropwise adding is finished, after the room temperature reaction is finished, concentrating the reaction liquid, adding 200ml of dichloromethane, neutralizing with sodium bicarbonate solution, washing with water and saturated sodium chloride, drying over night over anhydrous magnesium sulfate, filtering, concentrating the filtrate, adding isopropanol into the concentrate for recrystallization, crystallizing at 0-5 ℃, filtering, and drying under reduced pressure at 40-50 ℃ to obtain 21.4g, wherein the yield is 80%.
(2) Synthesis of Z-isomer impurity and impurity X
Adding 13.4g of a compound shown as a formula III (R is trifluoroacetyl group) and 11.5g of a compound shown as a formula IV into 150ml of N-methylpyrrolidone, adding 13g of N, N-diisopropylethylamine, reacting at 120 ℃, concentrating under reduced pressure to obtain a solvent and redundant catalyst, adding 50ml of methanol, separating out a solid, filtering, adding 4.5g of methanesulfonic acid into a filtrate to form a salt, separating out a small amount of solid, crystallizing the filtrate at 0-5 ℃ for more than 48 hours, filtering, drying the solid under reduced pressure to obtain 0.8g of an impurity X, concentrating the filtrate to one third of the volume, crystallizing at 0-5 ℃, filtering, drying under reduced pressure to obtain 2.5g of a Z-isomer impurity
HPLC detection conditions:
the instrument model is as follows: waters2695 model
Chromatographic conditions are as follows: the chromatographic column is Agilent ZORBAX Eclipse XDB-phenyl, and the mobile phase is A: 10mg of monopotassium phosphate, and adjusting the pH value to 3.0 by phosphoric acid; mobile phase B: acetonitrile, flow rate 1ml/min, detection wavelength: 260nm, and gradient elution is adopted, wherein the gradient conditions are as follows:
| time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 15 | 85 |
| 25 | 90 | 10 |
| 25.1 | 15 | 85 |
The instrument comprises the following steps: AVANCE III 500M full-digital superconducting nuclear magnetic resonance spectrometer
Analysis parameters: a probe: 5mm PABBO BB-1H/D Z-GRD Z119470/0010, temperature: 25 ℃;
500 MHz; sensitivity 450: 1; resolution 0.5Hz
1H spectrum:
z-isomer impurity:1H-NMR(DMSO-d6，400MHz)：δ＝5.96～5.99(d，1H)、6.68～6.69(d，1H)
e-isomer (rilpivirine):1H-NMR(DMSO-d6，400MHz)：δ＝6.43～6.47(d，1H)、8.01～8.03(d，1H)
impurity X:1H-NMR(DMSO-d6，400MHz)：δ＝1.91(s，6H)，6.42～6.46(d，1H)，6.82～6.84(d，1H)，7.24～7.33(d，2H)，7.40～7.42(d，2H)，7.51～7.55(d，2H)，7.70～7.74(d，2H)，8.00～8.13(d，2H)，8.27～8.28(d，2H)，10.57(s，1H)，11.77(s，1H)
the instrument comprises the following steps: bruker APEX IV Fourier transform cyclotron resonance mass spectrometer
Analysis parameters: capillary Voltage: -3800V Spray Shield Voltage: 3300V
Dry Gas Temperature：200℃
Z isomer impurity: m/z, 367.15[ M + H]+
Impurity X: m/z, 561.54[ M + H]+
Example 2 preparation of impurity X and isomer Z
(1) The synthesis of the compound of formula III (R is trifluoromethanesulfonyl) is as follows:
adding 117.2 g of the compound shown in the formula V into 20ml of tetrahydrofuran, adding 10.1g (1eq) of triethylamine, cooling to-5 ℃, dropwise adding 28.2g (1eq) of trifluoromethanesulfonic anhydride, controlling the temperature in the dropwise adding process to be less than 10 ℃, completing the dropwise adding, reacting at room temperature, concentrating the reaction solution, adding 300ml of ethyl acetate, neutralizing with a sodium bicarbonate solution, washing with water and saturated sodium chloride, drying over night with anhydrous magnesium sulfate, filtering, concentrating the filtrate, adding acetone into the concentrate for recrystallization, crystallizing at 0-5 ℃, filtering, drying at 40-50 ℃ under reduced pressure to obtain 26.1g, wherein the yield is 86%.
(2) Synthesis of Z-isomer impurity and impurity X
Adding 15.2g of a compound shown as a formula III (R is trifluoromethanesulfonyl) and 11.5g of a compound shown as a formula IV into 120ml of isopropanol, adding 16.8g of potassium tert-butoxide, reacting at 100 ℃, filtering, concentrating the filtrate under reduced pressure, adding 100ml of n-butanol, precipitating a solid, filtering, adding 10ml of hydrobromic acid into the filtrate to form a salt, crystallizing at 0-5 ℃ for more than 48 hours, filtering, drying the solid under reduced pressure to obtain 0.6g of an impurity X, concentrating the filtrate to be dry, carrying out column chromatography on an oily concentrate, eluting with methanol-water (1: 5), and concentrating the eluent to be dry to obtain 0.5g of Z-isomer
Example 3 preparation of impurity X and isomer Z
(1) The synthesis method of the compound shown in the formula III (R is p-methyl benzenesulfonyl) is as follows:
adding 117.2 g of the compound shown in the formula V into 30ml of acetone, adding 10.1g (1eq) of triethylamine, cooling to 0 ℃, dropwise adding 19g (1eq) of p-toluenesulfonyl chloride, controlling the temperature in the dropwise adding process to be less than 10 ℃, after the dropwise adding is finished, after the room temperature reaction is finished, concentrating the reaction liquid, adding 500ml of methyl tert-butyl ether, neutralizing with a sodium bicarbonate solution, washing with water and saturated sodium chloride, drying over night with anhydrous magnesium sulfate, filtering, concentrating the filtrate, adding acetone into the concentrate for recrystallization, crystallizing at 0-5 ℃, filtering, and drying under reduced pressure at 40-50 ℃ to obtain 26.7g, wherein the yield is 82%.
(2) Synthesis of Z-isomer impurity and impurity X
Adding 16.3g of a compound shown as a formula III (R is p-methylbenzenesulfonyl) and 11.5g of a compound shown as a formula IV into 150ml of N, N-dimethylformamide, adding 29.7g of potassium carbonate, reacting at 150 ℃, filtering, concentrating the filtrate under reduced pressure, adding 60ml of ethanol, separating out a solid, filtering, adding 11.6g of fumaric acid into the filtrate to form a salt, crystallizing at 0-5 ℃ for more than 48 hours, filtering, drying the solid under reduced pressure to obtain 0.2g of an impurity X, concentrating the filtrate to be dry, carrying out column chromatography on an oily concentrate, eluting with acetonitrile-water (3: 5), and concentrating the eluent to be dry to obtain 0.8g of Z-isomer impurity
Example 4 preparation of impurity X and isomer Z
(1) The synthesis method of the compound shown in the formula III (R is nitrobenzoyl) is as follows:
adding 117.2 g of the compound shown in the formula V into 30ml of 2-methyltetrahydrofuran, adding 10.1g (1eq) of triethylamine, cooling to 0 ℃, dropwise adding 18.5g (1eq) of nitrobenzoyl chloride, controlling the temperature in the dropwise adding process to be less than 10 ℃, completing the dropwise adding, finishing the reaction at room temperature, concentrating the reaction liquid, adding 500ml of ethyl acetate, neutralizing with a sodium bicarbonate solution, washing with water and saturated sodium chloride, drying over night with anhydrous magnesium sulfate, filtering, concentrating the filtrate, adding acetone into the concentrate for recrystallization, crystallizing at 0-5 ℃, filtering, drying at 40-50 ℃ under reduced pressure to obtain 27.2g, wherein the yield is 85%.
(2) Synthesis of Z-isomer impurity and impurity X
Adding 16g of a compound shown as a formula III (R is nitrobenzoyl) and 11.5g of a compound shown as a formula IV into 120ml of 2-methyltetrahydrofuran, adding 21g of sodium carbonate, reacting at 90 ℃, filtering, concentrating the filtrate under reduced pressure, adding 60ml of ethanol, separating out a solid, filtering, adding 11.6g of maleic acid into the filtrate to form a salt, crystallizing for more than 48 hours at 0-5 ℃, filtering, drying the solid under reduced pressure to obtain 0.5g of an impurity X, concentrating the filtrate to be dry, carrying out preparative liquid phase separation on an oily concentrate, carrying out mobile phase methanol-acetonitrile-water (2: 3: 5), and concentrating the eluent to be dry to obtain 1.2g of Z-isomer
EXAMPLE 5 preparation of impurity X and isomer Z
(1) The synthesis method of the compound shown in the formula III (R is trichloroacetyl) is as follows:
adding 117.2 g of the compound shown in the formula V into 20ml of acetonitrile, adding 10.1g (1eq) of triethylamine, cooling to 0 ℃, dropwise adding 21g (1eq) of trichloroacetic anhydride, controlling the temperature in the dropwise adding process to be less than 20 ℃, after dropwise adding, after the reaction at room temperature is finished, concentrating the reaction liquid, adding 200ml of dichloromethane, neutralizing with sodium bicarbonate solution, washing with water and saturated sodium chloride, drying over night over anhydrous magnesium sulfate, filtering, concentrating the filtrate, adding ethanol into the concentrate for recrystallization, crystallizing at 0-5 ℃, filtering, and drying under reduced pressure at 40-50 ℃ to obtain 27.4g of the compound shown in the formula V, wherein the yield is 87%.
(2) Synthesis of Z-isomer impurity and impurity X
Adding 15.3g of a compound shown as a formula III (R is trichloroacetyl) and 11.5g of a compound shown as a formula IV into 150ml of acetonitrile, adding 21g of sodium carbonate, reacting at 80 ℃, filtering, concentrating the filtrate under reduced pressure, adding 80ml of isopropanol, separating out solids, filtering, adding 6.3g of oxalic acid into the filtrate to form salt, separating out a small amount of solids, filtering the filtrate to crystallize for more than 48 hours at 0-5 ℃, filtering, drying the solids under reduced pressure to obtain 1.1g of impurities X, concentrating the filtrate to one third of the volume, crystallizing at 0-5 ℃, filtering, drying under reduced pressure to obtain 1.3g of Z-isomer impurities
EXAMPLE 6 preparation of impurity X and isomer Z
(1) The synthesis method of the compound shown in the formula III (R is trichloroacetyl) is as follows:
adding 117.2 g of the compound shown in the formula V into 20ml of acetonitrile, adding 10.1g (1eq) of triethylamine, cooling to 0 ℃, dropwise adding 21g (1eq) of trichloroacetic anhydride, controlling the temperature in the dropwise adding process to be less than 20 ℃, after dropwise adding, after the reaction at room temperature is finished, concentrating the reaction liquid, adding 200ml of dichloromethane, neutralizing with sodium bicarbonate solution, washing with water and saturated sodium chloride, drying over night over anhydrous magnesium sulfate, filtering, concentrating the filtrate, adding ethanol into the concentrate for recrystallization, crystallizing at 0-5 ℃, filtering, and drying under reduced pressure at 40-50 ℃ to obtain 27.4g of the compound shown in the formula V, wherein the yield is 87%.
(2) Synthesis of Z-isomer impurity and impurity X
Adding 15.3g of a compound shown as a formula III (R is trichloroacetyl) and 11.5g of a compound shown as a formula IV into 120ml of ethanol, adding 16.8g of potassium tert-butoxide, reacting at 60 ℃, filtering, concentrating the filtrate under reduced pressure, adding 60ml of ethanol, precipitating a solid, filtering, adding 10ml of hydrochloric acid into the filtrate to form a salt, precipitating a small amount of solid, filtering the filtrate to crystallize for more than 48 hours at 0-5 ℃, filtering, drying the solid under reduced pressure to obtain an impurity X0.7g, concentrating the filtrate to one third of the volume, crystallizing at 0-5 ℃, filtering, and drying under reduced pressure to obtain 1.1g of Z-isomer impurity
Example 7 evaluation of pesticidal Effect of impurity X
The soil quality of a certain vegetable greenhouse is sandy soil, the fertility is moderate, and the root knot nematode disease is serious. A land (with serious pests) is randomly selected in the vegetable greenhouse and divided into 6 cells, wherein each cell is 30m2 and the cells are randomly arranged. The 6 cells were divided into two groups, an example group and a blank control group (water), respectively. After 7-8 months of vegetable harvest, farmyard manure was applied and plowed. 1kg of the corresponding test agent was applied to each plot prior to vegetable transplantation. Sampling is carried out at 3 points in each cell, and 3 crops are respectively selected at each point and the right east, south, west and north directions of each point. After the vegetables are ripe and collected, observing and recording the disease index and the relative control effect of the vegetable roots.
Root disease index ═ Σ (number of disease roots at each stage × relative stage value)/total number of investigation × 5 × 100;
relative control effect (%) - (control root disease index-treatment root disease index)/control root disease index × 100.
The test results are given in table 1 below:
TABLE 1
| Grouping | Index of disease condition of root | Relative control effect (%) |
| |
3.5 | 80.6 |
| |
2.8 | 82.4 |
| Test article group 3 | 2.4 | 82.9 |
| |
35.6 | - |
| |
32.5 | - |
| Blank control group 3 | 30.7 | - |
The embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict with each other, for the limitation of the present invention. The protection scope of the present invention is defined by the claims, and includes equivalents of technical features of the claims. I.e., equivalent alterations and modifications within the scope hereof, are also intended to be within the scope of the invention.
Claims (13)
1. An impurity X of rilpivirine hydrochloride is characterized in that: the impurity X has a structure shown in (II):
2. the method for preparing rilpivirine hydrochloride impurity X of claim 1, characterized in that: the rilpivirine hydrochloride impurity X is obtained by separating reaction liquid during rilpivirine preparation;
the preparation route of rilpivirine is as follows:
the R group is trifluoroacetyl or trichloroacetyl or trifluoromethanesulfonyl or p-toluenesulfonyl or nitrobenzoyl.
3. The method of claim 2, wherein: the catalyst base used for preparing rilpivirine is potassium carbonate, sodium carbonate, potassium tert-butoxide or N, N-diisopropylethylamine.
4. The method of claim 2, wherein: the reaction solvent of rilpivirine is ethanol, isopropanol, acetonitrile, N-methylpyrrolidone, N-dimethylformamide, N-dimethylacetamide, 2-methyltetrahydrofuran or ethylene glycol dimethyl ether.
5. The method of claim 2, wherein: the reaction temperature for preparing rilpivirine is 60-150 ℃.
6. The method of claim 2, wherein: and after alkali and rilpivirine in the reaction solution of rilpivirine are filtered out, salt is formed between the filtrate and acid.
7. The method of claim 6, wherein: the acid comprises hydrochloric acid or hydrobromic acid or sulphuric acid or methanesulphonic acid or oxalic acid or fumaric acid or maleic acid.
8. The method of claim 2, wherein: the method also comprises the separation and purification of the rilpivirine hydrochloride impurity X, wherein the separation and purification method is any one or the combination of recrystallization, column chromatography and preparative liquid phase separation refining.
9. The method of claim 8, wherein: the solvent for recrystallization is alcohol.
10. The method of claim 9, wherein: the alcohol is one or the combination of methanol, ethanol, isopropanol and n-butanol.
11. The method of claim 8, wherein: the refining conditions of column chromatography and preparative liquid phase separation are that the eluent or mobile phase is any one or the combination of methanol-water, acetonitrile-water and methanol-acetonitrile-water, isocratic or gradient elution is carried out, the product fractions are collected and evaporated to dryness or freeze drying is carried out, thus obtaining the product.
12. The use of rilpivirine hydrochloride impurity X of claim 1 as a standard or control for qualitative or quantitative applications.
13. The use of rilpivirine hydrochloride impurity X as described in claim 1 or rilpivirine hydrochloride impurity X prepared by the methods of claims 2-11 as a pesticide in agriculture.
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| Atropisomerism in Rilpivirine hydrochloride: Spectroscopic characterization of Rilpivirine and related impurities;Senthilkumar Natarajan，等;《Chirality》;20180604;第30卷(第8期);第966-973页 * |
| Senthilkumar Natarajan，等.Atropisomerism in Rilpivirine hydrochloride: Spectroscopic characterization of Rilpivirine and related impurities.《Chirality》.2018,第30卷(第8期),第966-973页. * |
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