CN1267669A - 氨氯地平对映体的拆分 - Google Patents
氨氯地平对映体的拆分 Download PDFInfo
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- 229960000528 amlodipine Drugs 0.000 title claims abstract description 18
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 title claims abstract description 15
- 238000000926 separation method Methods 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 10
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims abstract description 9
- HTIQEAQVCYTUBX-QGZVFWFLSA-N (R)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-QGZVFWFLSA-N 0.000 claims abstract description 8
- 239000012069 chiral reagent Substances 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims description 6
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical class N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 4
- 238000001556 precipitation Methods 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- -1 muriate Chemical class 0.000 claims description 2
- 150000003462 sulfoxides Chemical class 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 150000001412 amines Chemical class 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- RSXGUJLKWYUPMC-UHFFFAOYSA-N flordipine Chemical compound CC1=C(C(=O)OCC)C(C=2C(=CC=CC=2)C(F)(F)F)C(C(=O)OCC)=C(C)N1CCN1CCOCC1 RSXGUJLKWYUPMC-UHFFFAOYSA-N 0.000 claims 1
- 229950009366 flordipine Drugs 0.000 claims 1
- 150000002632 lipids Chemical class 0.000 claims 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 abstract 1
- 235000002906 tartaric acid Nutrition 0.000 abstract 1
- 239000011975 tartaric acid Substances 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229910052757 nitrogen Inorganic materials 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- 238000003756 stirring Methods 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 229940095064 tartrate Drugs 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- 238000005194 fractionation Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供一个可行的拆分消旋氨氯地平的两个(R)-(+)-和(S)-(-)-对映体的方法,拆分用的手性试剂是酒石酸,拆分用的手性助剂是六氘代二甲基亚砜(DMSO-d6)。
Description
本发明提供一个可行的拆分消旋氨氯地平的两个(R)-(+)-和(S)-(-)-对映体的方法,拆分用的手性试剂是酒石酸,拆分用的手性助剂是六氘代二甲基亚砜(DMSO-d6)。
1.背景
(S)-(-)-氨氯地平 (R)-(+)-氨氯地平
辉瑞公司(Pfizer)发明了一个氨氯地平对映体的拆分可行方法(WO95/25722),其光学纯度和收率都非常高。该方法的关键是同时应用二甲基亚砜(DMSO)及手性试剂酒石酸。
本发明指出六氘代二甲基亚砜(DMSO-d6)是一种比DMSO还好的手性助剂,其光学纯度可达100%e.e.,并且收率也相当高。
2.发明
本发明提供了一个可行的拆分消旋氨氯地平的的方法,拆分用的手性试剂是L-酒石酸或D-酒石酸,拆分用的手性助剂是六氘代二甲基亚砜(DMSO-d6),氨氯地平和酒石酸的摩尔比大约是1∶0.25,发生的沉淀是(S)-(-)-氨氯地平-半-D-洒石酸-单-DMSO-d6配合物或(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物。
用于沉淀物的分离方法有过滤,离心分离或移注。
沉淀物的进一步处理可以得到(R)-(+)-氨氯地平或(S)-(-)-氨氯地平。
除去沉淀物后的母液可以用0.25当量相反极性的酒石酸(如首先用L-酒石酸,现在则用D-酒石酸)处理,相反极性的氨氯地平及其酒石酸和DMSO-d6配合物可生成沉淀。
拆分的溶剂是亚砜、酮、醇、醚、酰胺、酯、氯代烃、水、腈和烃。常见的溶剂是DMSO-d6、DMSO、丙酮、甲乙酮、异丙醇、乙醚、四氢呋喃、N,N’-二甲基甲酰胺、N,N’-二甲基丙撑脲、乙酸乙酯、氯仿、二氯甲烷、1,2-二氯乙烷、1,1,1-三氯乙烷、乙腈和甲苯。
其中使用的某一溶剂的最大数量是变化的,一个技术熟练的人能够确定这一适当的比例。但DMSO-d6/氨氯地平≥1(摩尔比)。
用于酒石酸盐重结晶的溶剂是醇类,例如:甲醇。
由氨氯地平的盐制备氨氯地平所用的碱类是金属的氢氧化物、氧化物、碳酸盐和酰胺盐。氢氧化钠是最方便的。
结晶的沉淀物组成分别是(S)-(-)-氨氯地平-半-洒石酸-单-DMSO-d6和(R)-(+)-氨氯地平-半-洒石酸-单-DMSO-d6配合物。
3.关于实施例
在以下实施例中,样品的光学纯度由手性HPLC测定。用于分离的HPLC条件如下:手性柱Ultron ES-OVM,Ovomucoid-15cm,流速0.3ml/min,检测波长360nm,流动相磷酸氢二钠缓冲溶液(20mM,PH7)/己氰=80/20。样品溶于己氰/水=50/50中,浓度为0.3mg/ml。
实施例1 由(R,S)-氨氯地平制备(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物和(R)-(+)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物5g(R,S)-氨氯地平溶于22.9g的DMSO-d6中,然后加入含0.458g D-酒石酸(0.25摩尔当量)溶于22.9g的DMSO-d6溶液并同时搅拌,在一分钟内开始沉淀,室温下搅拌过夜。过滤后,再用20ml丙酮洗涤,沉淀物在50℃下真空干燥过夜,得2.36g(理论收率的68%)(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物,m.p.158-160℃,(发现:C 50.81%,H(D)7.09%,N 4.84%,C20H25N2O5Cl·0.5[C4H6O6]·C2D6OS的计算值:C 50.74%,H(D)7.04%,N 4.90%),光学纯度99.9%d.e.(手性HPLC)。
0.44g L-酒石酸(0.25摩尔当量)加入过滤液中,室温下搅拌过夜。过滤再用20ml丙酮洗涤,沉淀物在50℃下真空干燥过夜,得2.0g(理论收率的55%)(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物,m.p.158-160℃,(发现:C 50.67%,H(D)6.95%,N 4.90%,C20H25N2O5Cl·0.5[C4H6O6]·C2D6OS的计算值:C 50.74%,H(D)7.04%,N 4.93%,光学纯度99.5%d.e.(手性HPLC)。
实施例2 由(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物制备(S)-(-)-氨氯地平5g(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物和56ml 2N NaOH水溶液与56ml CH2Cl2一起搅拌40分钟。用水洗涤分离后的有机溶液蒸除CH2Cl2,加入己烷并搅拌使其结晶。过滤后的固体经50℃真空过夜干燥得3.20g(理论收率的88%)(S)-(-)-氨氯地平,m.p.107-110℃,(发现:C 58.69%,H 6.09%,N 6.84%;C20H25N2O5Cl的计算值:C 58.75%,H 6.16%,N 6.85%),[α]D 25-32.6°(C=1,MeOH),光学纯度99.9%e.e.(手性HPLC)。
实施例3由(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物制备(R)-(+)-氨氯地平5g(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物和56ml 2N NaOH水溶液与56ml CH2Cl2一起搅拌40分钟。用水洗涤分离后的有机溶液蒸除CH2Cl2,加入己烷并搅拌使其结晶。过滤后的固体经50℃真空过夜干燥得3.31g(理论收率的91%)(R)-(+)-氨氯地平,m.p.107-110℃,(发现:C 58.41%,H 6.05%,N6.62%;C20H25N2O5Cl的计算值:C 58.75%,H 6.16%,N 6.85%),[α]D 25+32.6°(C=1,MeOH),光学纯度99.5%e.e.(手性HPLC)。
实施例4 由(R,S)-氨氯地平制备(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物和(R)-(+)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物用实施例1的方法,但DMSO-d6用混合溶剂代替,并且DMSO-d6/氨氯地平≥1(摩尔比)。V溶剂/(VDMSO-d6+V溶剂)以百分比表示,(VDMSO-d6+V溶剂)/M=4~18,其中V,体积,ml溶剂;M,质量,g氨氯地平。按实施例2-3处理配合物给出(S)-(-)-氨氯地平和(R)-(+)-氨氯地平
表
*测试方法为手性HPLC。
溶剂 | 溶剂体积% | (S)-(-)-对映体%e.e.* | (R)-(+)-对映体e.e.* |
甲乙酮 | 2 | 99.0 | 98.7 |
甲苯 | 2 | 92.0 | 91.7 |
异丙醇 | 5 | 92.6 | 92.4 |
H2O | 10 | 98.5 | 98.4 |
二甲基甲酰胺 | 10 | 98.3 | 98.1 |
四氢呋喃 | 33 | 98.6 | 98.5 |
乙酸乙酯 | 50 | 99.2 | 99.1 |
二氯甲烷 | 50 | 100 | 99.8 |
DESO | 50 | 98.1 | 98.4 |
DESO | 72 | 91.1 | 90.5 |
DMSO | 90 | 94.5 | 94.1 |
丙酮 | 50 | 99.2 | 99.0 |
丙酮 | 70 | 95.7 | 96.1 |
丙酮 | 90 | 95.4 | 95.7 |
丙酮 | 97 | 96.8 | 96.5 |
丙酮 | 99 | 95.4 | 95.1 |
实施例5苯磺酸(S)-(-)-氨氯地平的制备5g(S)-(-)-氨氯地平置120ml水中,然后加入1.4g苯磺酸并搅拌,在氮气保护下加热至60℃。溶解后,停止搅拌并冷却至室温,结晶过夜。过滤后,再经20ml水洗涤,苯磺酸(S)-(-)-氨氯地平在50℃下真空干燥过夜,得6.2g(理论收率的90%),(发现:C 54.85%,H 5.15%,N 5.58%;C20H25N2O5Cl的计算值:C 54.72%,H 5.14%,N 5.34%),[α]D 25-24.9°(C=1,MeOH),光学纯度99.9%e.e.(手性HPLC)。
Claims (6)
1.本发明是从一个混合物中分离出氨氯地平的(R)-(+)-和(S)-(-)-异构体的方法。在含有手性助剂六氘代二甲基亚砜(DMSO-d6)的有机溶剂中,异构体的混合物同拆分手性试剂L-或D-酒石酸反应,结合一个DMSO-d6的(R)-(+)-氨氯地平的L-酒石酸盐,或结合一个DMSO-d6的(S)-(-)-氨氯地平的D-酒石酸盐而分别沉淀。
2.根据权利要求1,在这个方法所用的手性助剂是DMSO-d6。DMSO-d6/氨氯地平≥1(摩尔比)
3.根据权利要求1,在这个方法所用的是可以使含DMSO-d6配合物发生沉淀的溶剂。
4.根据权利要求3,这些溶剂是水、亚砜类、酮类、醇类、醚类、胺类、脂类、氯化物、氰类或碳氢化合物。
5.根据上述任一权利要求,每摩尔氨氯地平应用L-或D-酒石酸大约0.25摩尔。
6.根据上述任一权利要求,沉淀的配合物是(R)-(+)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物或(R)-(+)-氨氯地平-半-L-酒石酸-单-DMSO-d6配合物。
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN00102701A CN1100038C (zh) | 2000-02-21 | 2000-02-21 | 氨氯地平对映体的拆分 |
CA002416062A CA2416062C (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
US10/203,615 US6646131B2 (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
EP00981132A EP1258477B1 (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
DE60027476T DE60027476T2 (de) | 2000-02-21 | 2000-12-08 | Enantiomerentrennung von amlodipin |
AU2001218494A AU2001218494B2 (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
AU1849401A AU1849401A (en) | 2000-02-21 | 2000-12-08 | Resolution of the enantiomers of amlodipine |
PCT/CN2000/000538 WO2001060799A1 (fr) | 2000-02-21 | 2000-12-08 | Resolution d'enantiomeres d'amlidipine |
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CN00102701A CN1100038C (zh) | 2000-02-21 | 2000-02-21 | 氨氯地平对映体的拆分 |
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US (1) | US6646131B2 (zh) |
EP (1) | EP1258477B1 (zh) |
CN (1) | CN1100038C (zh) |
AU (2) | AU1849401A (zh) |
CA (1) | CA2416062C (zh) |
DE (1) | DE60027476T2 (zh) |
WO (1) | WO2001060799A1 (zh) |
Cited By (6)
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WO2003043989A1 (en) * | 2001-11-22 | 2003-05-30 | Xitian Zhang | Hydrophilic (s)-amlodipine salts or their hydrates and pharmaceutical compositions |
CN100364976C (zh) * | 2002-09-11 | 2008-01-30 | 韩林制药株式会社 | S-(-)-氨氯地平的制备方法 |
CN100436417C (zh) * | 2006-04-11 | 2008-11-26 | 石药集团中奇制药技术(石家庄)有限公司 | 一种光学活性氨氯地平的拆分方法 |
CN104151229A (zh) * | 2014-07-30 | 2014-11-19 | 施慧达药业集团(吉林)有限公司 | 一种(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物的制备方法 |
CN111777547A (zh) * | 2020-07-17 | 2020-10-16 | 江西施美药业股份有限公司 | 一种诱导析晶拆分左旋氨氯地平的方法 |
CN112079770A (zh) * | 2020-10-05 | 2020-12-15 | 湖南理工学院 | 用于高效手性拆分及母液原位再生的循环萃取和非对映体结晶耦合新方法 |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2005509637A (ja) | 2001-10-24 | 2005-04-14 | セプラコア インク. | アムロジピンラセミ体の分離方法 |
CN1231469C (zh) * | 2003-12-05 | 2005-12-14 | 石家庄制药集团欧意药业有限公司 | 一种光学活性氨氯地平的拆分方法 |
KR101130622B1 (ko) * | 2004-10-20 | 2012-04-02 | 엠큐어 파마슈티컬즈 리미티드 | 높은 광학적 순도로 암로디핀의 광학이성질체를 제조하는방법 |
EP1831166B1 (en) * | 2004-12-02 | 2010-10-20 | SK Chemicals, Co., Ltd. | Optical resolution method of amlodipine |
KR101235116B1 (ko) * | 2005-10-17 | 2013-02-20 | 에스케이케미칼주식회사 | 광학활성 암로디핀 겐티세이트 염의 제조방법 |
KR100828883B1 (ko) * | 2006-10-27 | 2008-05-09 | 씨제이제일제당 (주) | 라세믹 암로디핀으로부터 s-(-)-암로디핀의 분리방법 |
US20090247750A1 (en) * | 2008-03-28 | 2009-10-01 | Biocryst Pharmaceuticals, Inc. | Process for preparing nucleoside analogs |
CN101766611B (zh) | 2010-02-09 | 2011-10-12 | 施慧达药业集团(吉林)有限公司 | 一种左旋氨氯地平或其可药用盐和β受体阻滞剂的药物组合物及其应用 |
EP3960158A1 (en) | 2016-10-07 | 2022-03-02 | Silvergate Pharmaceuticals, Inc. | Amlodipine formulations |
JP7456933B2 (ja) | 2018-04-11 | 2024-03-27 | シルバーゲイト ファーマシューティカルズ,インク. | アムロジピン製剤 |
KR20220005073A (ko) * | 2019-05-02 | 2022-01-12 | 클로즈드 룹 메디신 엘티디 | 환자에게 개인 맞춤 약물을 제공하기 위한 방법 및 시스템 |
CN110882249B (zh) | 2019-11-08 | 2021-04-30 | 北京吾为尔创科技有限公司 | 含苯磺酸左氨氯地平水合物的组合物及其制备方法 |
CN111100064B (zh) * | 2020-01-08 | 2024-01-02 | 湖南理工学院 | 一种从废液中富集、回收和拆分碱性手性药物氨氯地平的方法 |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8804630D0 (en) | 1988-02-27 | 1988-03-30 | Pfizer Ltd | Preparation of r-& s-amlodipine |
JPH01220075A (ja) * | 1988-02-29 | 1989-09-01 | Nippon Taisanbin Kogyo Kk | 表示部読取方法 |
GB9405833D0 (en) * | 1994-03-24 | 1994-05-11 | Pfizer Ltd | Separation of the enantiomers of amlodipine |
-
2000
- 2000-02-21 CN CN00102701A patent/CN1100038C/zh not_active Expired - Fee Related
- 2000-12-08 AU AU1849401A patent/AU1849401A/xx active Pending
- 2000-12-08 AU AU2001218494A patent/AU2001218494B2/en not_active Ceased
- 2000-12-08 EP EP00981132A patent/EP1258477B1/en not_active Expired - Lifetime
- 2000-12-08 US US10/203,615 patent/US6646131B2/en not_active Expired - Fee Related
- 2000-12-08 WO PCT/CN2000/000538 patent/WO2001060799A1/zh active IP Right Grant
- 2000-12-08 CA CA002416062A patent/CA2416062C/en not_active Expired - Fee Related
- 2000-12-08 DE DE60027476T patent/DE60027476T2/de not_active Expired - Fee Related
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003043989A1 (en) * | 2001-11-22 | 2003-05-30 | Xitian Zhang | Hydrophilic (s)-amlodipine salts or their hydrates and pharmaceutical compositions |
CN100364976C (zh) * | 2002-09-11 | 2008-01-30 | 韩林制药株式会社 | S-(-)-氨氯地平的制备方法 |
CN100436417C (zh) * | 2006-04-11 | 2008-11-26 | 石药集团中奇制药技术(石家庄)有限公司 | 一种光学活性氨氯地平的拆分方法 |
CN104151229A (zh) * | 2014-07-30 | 2014-11-19 | 施慧达药业集团(吉林)有限公司 | 一种(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物的制备方法 |
CN104151229B (zh) * | 2014-07-30 | 2015-04-22 | 施慧达药业集团(吉林)有限公司 | 一种(S)-(-)-氨氯地平-半-D-酒石酸-单-DMSO-d6配合物的制备方法 |
CN111777547A (zh) * | 2020-07-17 | 2020-10-16 | 江西施美药业股份有限公司 | 一种诱导析晶拆分左旋氨氯地平的方法 |
CN112079770A (zh) * | 2020-10-05 | 2020-12-15 | 湖南理工学院 | 用于高效手性拆分及母液原位再生的循环萃取和非对映体结晶耦合新方法 |
CN112079770B (zh) * | 2020-10-05 | 2024-01-02 | 湖南理工学院 | 用于高效手性拆分及母液原位再生的循环萃取和非对映体结晶耦合新方法 |
Also Published As
Publication number | Publication date |
---|---|
WO2001060799A1 (fr) | 2001-08-23 |
EP1258477B1 (en) | 2006-04-19 |
EP1258477A4 (en) | 2003-04-02 |
DE60027476T2 (de) | 2006-12-07 |
AU2001218494B2 (en) | 2006-09-28 |
EP1258477A1 (en) | 2002-11-20 |
CA2416062A1 (en) | 2002-11-06 |
CA2416062C (en) | 2009-02-17 |
DE60027476D1 (de) | 2006-05-24 |
AU1849401A (en) | 2001-08-27 |
US20030028031A1 (en) | 2003-02-06 |
US6646131B2 (en) | 2003-11-11 |
CN1100038C (zh) | 2003-01-29 |
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