CN1915974A - Method for splitting Amlodipine - Google Patents

Method for splitting Amlodipine Download PDF

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CN1915974A
CN1915974A CN 200510028964 CN200510028964A CN1915974A CN 1915974 A CN1915974 A CN 1915974A CN 200510028964 CN200510028964 CN 200510028964 CN 200510028964 A CN200510028964 A CN 200510028964A CN 1915974 A CN1915974 A CN 1915974A
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amlodipine
tartrate
methyl pyrrolidone
splitting
methyl
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CN100532358C (en
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王涛
林国强
甘益民
周庆武
邱雪飞
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Jiangsu Haici Biological Pharmaceutical Co., Ltd. of Yangtze River Pharmaceutical Group
Shanghai Haini Pharm Co., Ltd., Yangzijiang Pharm Group
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Shanghai Haini Pharm Co Ltd Yangzijiang Pharm Group
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Abstract

This invention discloses a method for resolving amlodipine. The method uses tartaric acid as the chiral reagent, and N-methylpyrrolidone as the chiral aid. The method has such advantages as high resolving rate, high product optic purity and simple process, and is suitable for mass production.

Description

The method for splitting of amlodipine
Technical field
The invention belongs to the pharmaceutical chemistry technical field.Be specifically related to the method for splitting of amlodipine.
Background technology
The invention provides a pair of S-(-)-amlodipine of fractionation racemic amlodipine and the method for R-(+)-amlodipine enantiomorph.
(S-(-)-amlodipine) is the third generation dihydropyridines calcium preparation short of money of Pfizer company development to levamlodipine, at first goes on the market in Britain in nineteen ninety, continues mutually thereafter in Europe, the United States, day listing, China's approved import.Its hypertension effect is excellent, and diseases such as stenocardia and heart failure are also had better curative effect.With common calcium antagonist relatively, have the myocardial contraction rate that do not influence, long-acting, the side effect incidence is low, does not cause advantages such as reflex tachycardia.
Compare with levamlodipine, its dextrorotatory isomer (R-(+) though-amlodipine) to lack the calcium channel blocking-up active, it is that effective smooth muscle cell moves inhibitor.It can be used for treating atherosclerosis, restenosis and endometriosis after the angioplasty.
Though two isomer of amlodipine all have good pharmacologically active, therefore but existing chemical synthesis process only can access the amlodipine of racemization, obtains two isomer levamlodipines respectively and dextrorotatory isomer becomes a problem extremely to be solved to splitting with the racemic amlodipine that obtains.Its method for splitting of existing bibliographical information in 1984,1994, researchdevelopment company of Pfizer invented and has used the tartrate separate mode, split levamlodipine (WO95/25722), and its optical purity (＞99%) and the yield of product are all very high.The key that this method is confined to is to utilize tartrate as chiral selectors, utilizes methyl-sulphoxide (DMSO) as chiral auxiliary(reagent).But this method can only obtain levamlodipine (S-(-)-amlodipine), and because the fusing point of methyl-sulphoxide is higher, will solidifying when being lower than 18 ℃.Make troubles thereby give to produce.
2003, Zhang Xitian was invented and has been utilized tartrate as resolution reagent, deuterated dimethyl sulfoxide (DMSO-d 6) as the method for splitting (CN 1100038C) of chiral auxiliary(reagent), can obtain two isomer of amlodipine simultaneously.But deuterated dimethyl sulfoxide (DMSO-d in this method 6) price is very high, and deuterated reagent has very big toxicity, bans use of in pharmaceutical industry, therefore do not have any prospects for commercial application.
The present invention points out that N-Methyl pyrrolidone is a kind of than methyl-sulphoxide (DMSO) and deuterated dimethyl sulfoxide (DMSO-d 6) be fit to industrial chiral auxiliary(reagent) more effectively, more.Its optical purity can be up to 99.8%, and yield is higher and operation is also convenient than above two kinds of methods, obtains to such an extent that crystalline form is very good.Therefore has better prospects for commercial application.
Summary of the invention
Technical problem to be solved by this invention is to overcome above-mentioned weak point, the research and design industrial amlodipine method for splitting that can suit.
The chiral reagent that splits usefulness in present method is D-tartrate or L-tartrate, the chiral auxiliary(reagent) that splits usefulness is a N-Methyl pyrrolidone, amlodipine and tartaric mol ratio are 1: 0.5 to 1: 0.55, and the mass ratio of racemic amlodipine and chiral auxiliary(reagent) N-Methyl pyrrolidone is 1: 2.The throw out of separating out is (S)-(-)-amlodipine-half-D-tartrate-list-N-Methyl pyrrolidone title complex or (R)-(+)-amlodipine-partly-L-tartrate-list-N-Methyl pyrrolidone title complex.
The method that the present invention splits amlodipine is, racemic amlodipine is dissolved in the N-Methyl pyrrolidone solution, tartaric N-Methyl pyrrolidone drips of solution is added reaction solution, amlodipine and D-or the reaction of L-tartrate, stirring at room 40 minutes-5 hours, add (S)-(-)-amlodipine-half-D-tartrate of trace or (R)-(+)-amlodipine-half-L-tartrate then as crystal seed, the static crystallization of room temperature 12 hours, make (S)-(-)-amlodipine-half-D-tartrate, or just separate out with the form of crystalline deposit in conjunction with (R)-(+)-amlodipine-half-L-tartrate of a solvent molecule in conjunction with a solvent molecule.Such throw out crystalline form is attractive in appearance, can conveniently be separated with filtration under diminished pressure or centrifugation method.
Mother liquor after the filtration continues to stir 24 hours in 5 ℃, is cooled to then about 5 degrees centigrade, and the tartrate solvent complex of the isomer of another amlodipine of opposite configuration then can precipitate separates out.
Splitting the adjuvant used amount and the effect of fractionation in the inventive method has very big relation, is listed as follows:
Racemic amlodipine charging capacity (gram) Obtain the amount (gram) of (S)-(-)-amlodipine-half-D-tartrate The amount of N-Methyl pyrrolidone (milliliter) Yield (%) E.e value (%)
11.42 5.2 100 64 99.7
11.42 5.9 80 72 99.0
11.42 6.0 60 74 98.0
11.42 6.2 40 80 97.5
11.42 6.5 35 81 93.8
11.42 7.0 30 86 81.9
Splitting used solvent is generally: ketone, sulfone, sulfoxide, acid amides, alcohol etc. commonly used are: N-Methyl pyrrolidone, N-ethyl pyrrolidone, acetone, DMF, DMA, DMSO, tetramethylene sulfone, ethanol, dipropyl sulfoxide etc.The mixed solvent of N-Methyl pyrrolidone and some common solvent also can be obtained extraordinary fractionation effect.Concrete split result situation sees the following form:
Solvent Solvent/N-Methyl pyrrolidone (%) Yield (%) E.e value (%)
64 99.7
Acetone 2 65 99.6
Acetone 5 64 99.6
Acetone 10 62 98.7
Methyl-sulphoxide 2 65 99.8
Methyl-sulphoxide 5 63 99.3
Methyl-sulphoxide 30 50 99.5
Methyl-sulphoxide 35 56 99.5
Methyl-sulphoxide 40 73 99.2
Methyl-sulphoxide 45 78 99.0
Methyl-sulphoxide 50 81 98.9
H 2O 1 65 99.8
H 2O 2 64 99.7
DMF 2 64 99.6
DMF 5 63 99.5
DMA 1 65 99.6
DMA 5 64 99.2
For (S)-(-)-amlodipine that obtains-half-D-tartrate or (R)-(+)-and amlodipine-half-L-tartrate solvent complex, generally need be through a recrystallization, recrystallization solvent commonly used is an alcohols, ketone.The most frequently used is methyl alcohol or ethanol and methyl-2-pyrrolidone.
Taking off tartrate by amlodipine tartarate salt alkaline hydrolysis prepares the used alkali of amlodipine and is generally alkali-metal oxyhydroxide, carbonate, supercarbonate such as sodium hydroxide, potassium hydroxide, yellow soda ash, salt of wormwood, sodium bicarbonate etc.We adopt the most frequently used sodium hydroxide to carry out basic hydrolysis in this patent.Amlodipine tartarate salt is 4: 1 with the ratio of the quality of sodium hydroxide when carrying out basic hydrolysis.
The composition of crystalline deposit thing is respectively (S)-(-)-amlodipine-half-D-tartrate-list-N-Methyl pyrrolidone title complex or (R)-(+)-amlodipine-partly-L-tartrate-list-N-Methyl pyrrolidone title complex.
The inventive method is easy, and it is cheap and easy to get to split agents useful for same, resolution yield height, optical purity of products＞99%.And be suitable for the scale suitability for industrialized production.
Embodiment
Embodiment 1 by (R, S)-amlodipine preparation (S)-(-)-amlodipine-half-D-tartrate-list-N-Methyl pyrrolidone title complex and (R)-(+)-amlodipine-partly-D-tartrate-list-N-Methyl pyrrolidone title complex
In one 250 milliliters of egg shape bottles, with 200 milliliters of N-Methyl pyrrolidone with 57 grams (R, S)-amlodipine dissolving.10.5 gram D-tartrate are dissolved in 200 milliliters of drips of solution in the N-Methyl pyrrolidone add in the reaction system room temperature placing response 1 hour.Adding trace (S)-(-)-amlodipine-half-the D-tartrate is as crystal seed, and room temperature continued static crystallization 12 hours.Filtration under diminished pressure, the white solid that obtains is washed with 50 milliliters of acetone, dry 10 hours of reduced vacuum.26 grams (theoretical yield 80%) (S)-(-)-amlodipine-half-D-tartrate-list-N-Methyl pyrrolidone title complex.
Compound 3-30
Molecular formula: C 27H 38O 7ClN 3O 9
Optical purity 99.3%d.e. (chirality HPLC)
m.p.123-125℃
In this example and following example, the optical purity of product is measured by chirality HPLC, it is as follows to be used for isolating HPLC condition: chiral column U ltron ES-OVM Ovomucoid-15cm flow velocity 0.3/min, detect wavelength 360um, moving phase disodium hydrogen phosphate buffer solution (20Mm, PH=7)/and second cyanogen=80/20, sample is dissolved in second cyanogen/water=50/50, concentration 0.3mg/ml.The fusing point instrument is the micro-fusing point instrument of Tyke, Beijing XT-4, and is not calibrated. 1H-NMR measures under room temperature on Varian EM-390 (90MHz), Bruker AM 300 (300MHz) or Varian Mercury 300 (300MHz) nuclear magnetic resonance analyser; Chemical shift (δ) is interior mark with tetramethylsilane, is unit representation with ppm; Order by peak type (three heavy peak is expressed as t for the unimodal s that is expressed as, the bimodal d that is expressed as, and quartet is expressed as q, and multiplet is expressed as m), hydrogen number, coupling constant (Hz) is reported.In 589nm, 20 ℃ of mensuration are expressed as [α] to specific rotation on Perkin-Elmer 341MC polarimeter D 20(solvent, concentration (gram/100mL)).Infrared analysis, mass spectroscopy, ultimate analysis and HPLC finish by Institute of Analysis of Shanghai organic chemistry institute: IR (Infraredresonance spectra) measures on Bio-Rad FTS-185 with the KBr compressing tablet, and unit is cm -1Low Resolution Mass Spectra (EI) is measured on HP HP5989A or Aglient HP5873.Ultimate analysis is finished on Elemantar Vario EL elemental analyser.
1H NMR(300Hz，CDCl 3)δ：7.99(s，1H)，7.34(d，1H，J＝7.8Hz)，7.16(d，1H，J＝7.8Hz)，7.06(t，1H，J＝7.2Hz)，6.94(t，1H，J＝7.5Hz)，5.34(s，1H)，4.69(q，2H，J＝6.9Hz)，4.42(s，1H)，3.96(m，2H)，3.72(s，2H)，3.52(s，3H)，3.39(t，2H，J＝7.2Hz)，3.17(s，2H)，2.85(s，3H)，2.38(t，2H，J＝7.8Hz)，2.28(s，3H)，2.04(m，2H)，1.11(t，3H，J＝6.9Hz)，；
IR(KBr)3300，1687，1486，1201，1099，757；
EIMS(m/z，％)408
EA, calculated value C:55.52% H:6.56% N:7.19%
Measured value C:55.47% H:6.37% N:7.17%
Mother liquor after the filtration continues to stir 24 hours, be cooled to then about 5 degrees centigrade, slowly there is solid to separate out, keep this temperature to stir 12 hours, filtration under diminished pressure, the white solid that obtains is washed with 50 milliliters of acetone, and vacuum-drying 12 hours gets 29 gram (R)-(+)-amlodipines-half-D-tartrate-list-N-Methyl pyrrolidone title complexs.
Molecular formula: C 27H 38O 7ClN 3O 9
m.p.127-129℃
1H NMR(300Hz，CDCl 3)δ：7.99(s，1H)，7.34(d，1H，J＝7.8Hz)，7.16(d，1H，J＝7.8Hz)，7.06(t，1H，J＝7.2Hz)，6.94(t，1H，J＝7.5Hz)，5.34(s，1H)，4.69(q，2H，J＝6.9Hz)，4.42(s，1H)，3.96(m，2H)，3.72(s，2H)，3.52(s，3H)，3.39(t，2H，J＝7.2Hz)，3.17(s，2H)，2.85(s，3H)，2.38(t，2H，J＝7.8Hz)，2.28(s，3H)，2.04(m，2H)，1.11(t，3H，J＝6.9Hz)，；
IR(KBr)3300，1687，1486，1201，1099，757；
EIMS(m/z，％)408
EA, calculated value C:55.52% H:6.56% N:7.19%
Measured value C:55.56% H:6.50% N:7.19%
Embodiment 2 by (R, S)-amlodipine preparation (R)-(+)-amlodipine-half-L-tartrate-list-N-Methyl pyrrolidone title complex and (S)-(-)-amlodipine-partly-L-tartrate-list-N-Methyl pyrrolidone title complex
In one 250 milliliters of egg shape bottles, with 50 milliliters of N-Methyl pyrrolidone with 11.84 grams (R, S)-amlodipine dissolving.4.2 gram L-tartrate are dissolved in 40 milliliters of drips of solution in the N-Methyl pyrrolidone add in the reaction system stirring at room reaction 5 hours.Add trace (R)-(+)-amlodipine-half-L-tartrate as crystal seed, room temperature continued stirring and crystallizing 12 hours.Filtration under diminished pressure, the white solid that obtains is washed with 50 milliliters of acetone, dry 10 hours of reduced vacuum.4.62 grams (theoretical yield 70%) (R)-(+)-amlodipine-half-L-tartrate-list-N-Methyl pyrrolidone title complex.
Compound 3-30
Molecular formula: C 27H 38O 7ClN 3O 9
m.p.124-126℃
1H NMR(300Hz，CDCl 3)δ：7.93(s，1H)，7.34(d，1H，J＝7.8Hz)，7.17(d，1H，J＝8.1Hz)，7.07(t，1H，J＝7.5Hz)，6.96(t，1H，J＝7.5Hz)，5.35(s，1H)，4.72(q，2H)，4.42(s，1H)，3.97(q，2H，J＝7.2Hz)，3.51(s，2H)，3.54(s，3H)，3.39(t，2H，J＝7.2Hz)，3.17(s，2H)，2.85(s，3H)，2.38(t，2H，J＝7.8Hz)，2.29(s，3H)，2.04(m，2H)，1.12(t，3H，J＝7.2Hz)；
IR(KBr)3350，2903，1703，1483，1205，1100，757；
EIMS(m/z，％)408
EA, calculated value C:52.54% H:6.21% N:5.57%
Measured value C:55.60% H:6.10% N:5.23%
Mother liquor after the filtration continues to stir 24 hours, be cooled to then about 5 degrees centigrade, slowly there is solid to separate out, keep this temperature to stir 12 hours, filtration under diminished pressure, the white solid that obtains is washed with 50 milliliters of acetone, and vacuum-drying 12 hours gets 4.3 gram (S)-(-)-amlodipines-half-L-tartrate-list-N-Methyl pyrrolidone title complexs.
Molecular formula: C 27H 38O 7ClN 3O 9
m.p.123-125℃
1H NMR(300Hz，CDCl 3)δ：7.99(s，1H)，7.34(d，1H，J＝7.8Hz)，7.16(d，1H，J＝7.8Hz)，7.06(t，1H，J＝7.2Hz)，6.94(t，1H，J＝7.5Hz)，5.34(s，1H)，4.69(q，2H，J＝6.9Hz)，4.42(s，1H)，3.96(m，2H)，3.72(s，2H)，3.52(s，3H)，3.39(t，2H，J＝7.2Hz)，3.17(s，2H)，2.85(s，3H)，2.38(t，2H，J＝7.8Hz)，2.28(s，3H)，2.04(m，2H)，1.11(t，3H，J＝6.9Hz)，；
IR(KBr)3300，1687，1486，1201，1099，757；
EIMS(m/z，％)408
EA, calculated value C:55.52% H:6.56% N:7.19%
Measured value C:55.47% H:6.37% N:7.17%
Embodiment 3 is by (S)-(-)-amlodipine-half-D-tartrate-list-N-Methyl pyrrolidone title complex preparation (S)-(-)-amlodipine (basic hydrolysis)
5 gram (S)-(-)-amlodipine-half-D-tartrate-list-N-Methyl pyrrolidone title complexs stirred 40 minutes with 15 milliliters of 2N aqueous sodium hydroxide solutions and 15 milliliters of methylene dichloride.Oily water separation, organic layer washes twice with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, sherwood oil displacement stirred crystallization obtains white solid, filtration under diminished pressure, vacuum-drying gets 3.2 gram (S)-(-)-amlodipines (theoretical yield 88%).
Molecular formula: C 20H 25O 7ClN 2O 5
m.p.110-111℃
[α] D＝-31.8°(c＝1.25，MeOH)
Optical purity 99.7%d.e. (chirality HPLC)
1H NMR(300Hz，CDCl 3)δ：7.96(s，1H)，7.31(d，1H，J＝7.8Hz)，7.15(d，1H，J＝7.8Hz)，7.06(t，1H，J＝7.5Hz)，6.97(t，1H，J＝7.2Hz)，5.33(s，1H)，4.68(m，2H)，3.97(t，2H，J＝7.8Hz)，3.55(s，3H)，3.52(m，2H)，2.88(m，2H)，2.28(s，3H)，1.29(s，2H)，1.12(t，3H，J＝8.4Hz)，；
IR(KBr)3372，3361，3038，1678，1608，1482，1210；
EIMS(m/z，％)208(41.99)，254(26.58)，297(100)，408(M+，2.23)
EA, calculated value C:58.41% H:6.16% N:6.58%
Measured value C:58.75% H:6.16% N:6.85%
Embodiment 4 is by (R)-(+)-amlodipine-half-L-tartrate-list-N-Methyl pyrrolidone title complex preparation (R)-(+)-amlodipine (basic hydrolysis)
5 gram (R)-(+)-amlodipine-half-L-tartrate-list-N-Methyl pyrrolidone title complexs stirred 40 minutes with 15 milliliters of 2N aqueous sodium hydroxide solutions and 15 milliliters of methylene dichloride.Oily water separation, organic layer washes twice with water, anhydrous sodium sulfate drying, concentrating under reduced pressure, sherwood oil displacement stirred crystallization obtains white solid, filtration under diminished pressure, vacuum-drying must restrain (R)-(+)-amlodipine of 2.6 grams.
Molecular formula: C 20H 25O 7ClN 2O 5
m.p.109-110℃
[α] D＝+35.1°(c＝1.31，MeOH)
1H NMR(300Hz，CDCl 3)δ：7.88(s，1H)，7.36(d，1H，J＝7.5Hz)，7.21(dd，1H，J 1＝7.8Hz，J 2＝0.6Hz)，7.115(t，1H，J＝8.4Hz)，7.02(t，1H，J＝7.5Hz)，5.39(s，1H)，4.73(dd，2H，J 1＝25.8Hz，J 2＝16.5Hz)，4.03(q，2H，J＝6.9Hz)，3.598(s，3H)，3.57(m，2H)，2.94(s，2H)，2.34(s，3H)，1.37(s，2H)，1.17(t，3H，J＝6.9Hz)，；
IR(KBr)3361，3372，1676，1482，1210，1104，1028，749，617；
EIMS(m/z，％)208(44.09)，254(21.58)，297(100)，408(M+，2.83)
EA, calculated value C:55.52% H:6.16% N:6.85%
Measured value C:55.59% H:6.21% N:6.59%
The preparation of embodiment 5 Phenylsulfonic acids (S)-(-)-Amlodipine
Say that 2 gram (S)-(-)-amlodipines place one 100 milliliters of reaction flasks, add 50 ml waters, add 560 milligrams of Phenylsulfonic acids then, heat 60 degrees centigrade and be stirred to dissolving fully.Stop stirring and be cooled to room temperature, place the crystallization of spending the night.Filtration under diminished pressure, gained solid washing, drying weigh 2.4 grams, one water Phenylsulfonic acid (S)-(-)-Amlodipine (theoretical yield 91%)
Molecular formula: C 26H 35O 7ClN 2O 10S
m.p.68-69℃
Optical purity 99.8%d.e. (chirality HPLC)
[α] D＝-24.8°(c＝1.31，MeOH)
1H NMR(300Hz，CDCl 3)δ：7.74(m，2H)，7.53(s，1H)，7.19-7.32(m，4H)，7.12(dd，1H，J 1＝7.5Hz，J 2＝1.5Hz)，6.89-7.01(m，2H)，5.24(s，1H)，4.92(br，6H)，4.50(dd，2H，J 1＝37.8Hz，J 2＝14.2Hz)，3.94(m，2H)，3.52(d，2H，J＝4.8Hz)，3.49(s，3H)，3.06(d，2H，J＝4.5Hz)，2.08(s，3H)，1.09(t，3H，J＝6.9Hz)，；
IR(KBr)3405，1689，1483，1211，1125，1069，1017，730，613，565；
EIMS(m/z，％)311(100)，313(76.10)，226(58.95)
EA, calculated value C:51.74% H:5.80% N:4.64%
Measured value C:51.62% H:5.97% N:4.64%

Claims (4)

1, a kind of method for splitting of amlodipine, this method comprises the following steps:
(1) racemic amlodipine is dissolved in N-Methyl pyrrolidone solution, drips tartaric N-Methyl pyrrolidone solution, stirring at room 40 minutes-5 hours;
(2) in reaction solution, add trace (S)-(-)-amlodipine-half-D-tartrate or (R)-(+) amlodipine-half-L-tartrate as crystal seed, the static crystallization of room temperature 12 hours;
(3) filter crystal, after solvent recrystallization, (S)-(-) amlodipine after obtaining splitting after the reduced vacuum drying or (R)-(+) half tartrate of amlodipine-list-N-Methyl pyrrolidone title complex;
(4) step (3) filtrate filtered obtains half tartrate-list of the amlodipine-N-Methyl pyrrolidone title complex of another optical configuration of step (3) crystalline opposite configuration after 5 ℃ of continuation are stirred 24 hours, makes highly finished product after recrystallization, drying;
(5) half tartrate-list of the amlodipine-N-Methyl pyrrolidone title complex of the optical configuration that obtains of step (3) or (4) makes the optical configuration chlorine Flordipine of fractionation after basic hydrolysis.
2, the method for splitting of a kind of amlodipine according to claim 1 is characterized in that wherein said step (1) amlodipine and tartaric mol ratio are 1: 0.5-1: 0.55, and the mass ratio of amlodipine and N-Methyl pyrrolidone is 1: 2.
3, the method for splitting of a kind of amlodipine according to claim 1 is characterized in that wherein said step (2) or (3) recrystallization solvent for use are methyl alcohol, ethanol or methyl-2-pyrrolidone.
4, the method for splitting of amlodipine according to claim 1, the alkali that it is characterized in that wherein said step (5) is sodium hydroxide, carbonate or supercarbonate.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101085169B1 (en) * 2009-03-25 2011-11-18 (주)켐트로스 Process for separating the enantiomers of amlodipine
CN111100064A (en) * 2020-01-08 2020-05-05 湖南理工学院 Method for enriching, recovering and splitting alkaline chiral drug amlodipine from waste liquid
CN111777547A (en) * 2020-07-17 2020-10-16 江西施美药业股份有限公司 Method for inducing crystallization and resolution of levamlodipine

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101085169B1 (en) * 2009-03-25 2011-11-18 (주)켐트로스 Process for separating the enantiomers of amlodipine
CN111100064A (en) * 2020-01-08 2020-05-05 湖南理工学院 Method for enriching, recovering and splitting alkaline chiral drug amlodipine from waste liquid
CN111100064B (en) * 2020-01-08 2024-01-02 湖南理工学院 Method for enriching, recovering and resolving alkaline chiral medicine amlodipine from waste liquid
CN111777547A (en) * 2020-07-17 2020-10-16 江西施美药业股份有限公司 Method for inducing crystallization and resolution of levamlodipine

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