CN1131203C - 一种分离曲马多外消旋体的方法 - Google Patents
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- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 title claims abstract description 22
- 229960004380 tramadol Drugs 0.000 title claims abstract description 19
- 238000000034 method Methods 0.000 title claims abstract description 15
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- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 14
- 239000001358 L(+)-tartaric acid Substances 0.000 claims description 12
- 235000011002 L(+)-tartaric acid Nutrition 0.000 claims description 12
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
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- 238000001556 precipitation Methods 0.000 claims description 3
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
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- 238000000926 separation method Methods 0.000 description 8
- 150000003892 tartrate salts Chemical class 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 6
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- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 5
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- 238000003756 stirring Methods 0.000 description 5
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- PPKXEPBICJTCRU-UHFFFAOYSA-N [2-hydroxy-2-(3-methoxyphenyl)cyclohexyl]methyl-dimethylazanium;chloride Chemical compound Cl.COC1=CC=CC(C2(O)C(CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-UHFFFAOYSA-N 0.000 description 3
- 238000003916 acid precipitation Methods 0.000 description 3
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- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
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- 239000005051 trimethylchlorosilane Substances 0.000 description 3
- WZUOPLJKHHHQRO-PJDOXHBJSA-N (2r,3r)-2,3-dihydroxybutanedioic acid;(1s,2s)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 WZUOPLJKHHHQRO-PJDOXHBJSA-N 0.000 description 2
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- YONLFQNRGZXBBF-KBPBESRZSA-N (2s,3s)-2,3-dibenzoyloxybutanedioic acid Chemical compound O([C@H](C(=O)O)[C@H](OC(=O)C=1C=CC=CC=1)C(O)=O)C(=O)C1=CC=CC=C1 YONLFQNRGZXBBF-KBPBESRZSA-N 0.000 description 1
- PPKXEPBICJTCRU-KUARMEPBSA-N (S,S)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-KUARMEPBSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- TVYLLZQTGLZFBW-UHFFFAOYSA-N 2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol Chemical compound COC1=CC=CC(C2(O)C(CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-UHFFFAOYSA-N 0.000 description 1
- OOKSMYZBWRKRGU-UHFFFAOYSA-N 2-benzoyl-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)C(O)C(O)(C(O)=O)C(=O)C1=CC=CC=C1 OOKSMYZBWRKRGU-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- WURBFLDFSFBTLW-UHFFFAOYSA-N benzil Chemical group C=1C=CC=CC=1C(=O)C(=O)C1=CC=CC=C1 WURBFLDFSFBTLW-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229960003107 tramadol hydrochloride Drugs 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/10—Separation; Purification; Stabilisation; Use of additives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pain & Pain Management (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种分离曲马多外消旋体的方法。
Description
本发明涉及一种分离曲马多外消旋体的方法。
盐酸曲马多-盐酸(1RS，2RS)-2-甲氨基甲基-1-(3-甲氧基苯基)-环己醇-在主要起作用的镇痛药中占有特殊地位，因为这种有效成分作为疼痛的强抑制剂而无众所周知的阿片样物质的副作用(J.Phannacol.Exp.Ther.
267，331(1993))。曲马多是一种外消旋体，由等量的(+)对映体和(-)对映体组成。大家知道，曲马多对映体的药剂外形很有趣，不同于曲马多。(+)对映体的特征为有鸦片样的镇痛效果，与曲马多相比镇痛效果显著增强，而(-)对映体则明显抑制去肾上腺素的吸收。
在Arzeneim.-Forsch./Drug Res.
28(I)，114(1978)中描述了用外消旋体分离试剂二苯甲酰-酒石酸制备曲马多对映体的方法。这种方法的缺点是使用非常昂贵的手性附加试剂二苯甲酰-酒石酸。由于这种化合物在非对映体盐的碱处理期间二苯甲酰基部分分离，因此该化合物在外消旋体分离中重新使用有相当大的困难。而且，曲马多对映体的分离需要二苯甲酰-酒石酸的光学对映体：要得到(+)曲马多对映体必须用(-)-O，O’-二苯甲酰-L-酒石酸进行沉淀；要得到(-)曲马多对映体必须用(+)-O，O’-二苯甲酰-D-酒石酸进行沉淀。
因此本发明的根本目的是研制出一种分离曲马多外消旋体的方法，用该方法可以得到稳定高产和高对映体纯度的曲马多对映体，从而避免众所周知的由于使用二苯甲酰-酒石酸而产生的缺点。
我们惊讶地发现，迫切需要研制的方法用便宜的L-(+)-酒石酸完成了。
因此，本发明涉及一种分离曲马多外消旋体的方法，其特征在于，将外消旋的曲马多盐转化为碱，用L-(+)-酒石酸沉淀来分离(-)曲马多对映体，而通过释放曲马多碱、再转化为不同于酒石酸盐的盐，从酒石酸沉淀的母液中分离(+)曲马多对映体。
外消旋的盐酸曲马多特别适于作为本发明方法的原材料。在水溶液中加入碱性氢氧化物、最好是氢氧化钠，将该物质转化为外消旋的曲马多，再用有机溶剂如二氯甲烷和/或乙醚进行提取。得到的碱随后用L-(+)-酒石酸处理，比较好的是在有机溶剂的存在下、最好是在脂族Cl-5醇的存在下进行。分离生成的曲马多(-)对映体的酒石酸盐，尤其是通过结晶，使其与生成的曲马多(+)对映体的酒石酸盐分开；如果需要的话，随后在上述条件下通过释放曲马多碱、并转化为不同于酒石酸盐的曲马多盐、最好转化为盐酸盐来分离生成的曲马多(-)对映体的酒石酸盐。
溶于母液中、以酒石酸盐形式存在的(+)曲马多对映体在上述条件下，通过释放碱，再转化为非酒石酸盐的盐、尤其是转化为曲马多的盐酸盐来进行分离。
可以用浓盐酸或气态氯化氢在有机溶剂中，例如在丙酮、二氧六环、乙醚和/或二异丙醚中，或用三甲基氯硅烷/水在溶剂如2-丁酮中，将曲马多碱转化为盐酸盐。
本发明的方法可以经济地、以环境友善的方式来实施。与用二苯甲酰-酒石酸的外消旋体分离方法相比，本发明的方法的区别在于，只有一种酒石酸的对映体形式、即便宜的L-(+)-酒石酸是分离外消旋体所必需的。用L-(+)-酒石酸，就使用的外消旋体而言，可以得到收率高于85％、对映体纯度高于98％的对映体。而且，L-(+)-酒石酸的分子量只有二苯甲酰-酒石酸的2.4分之一，其结果是生成的沉淀产物大大减少。另外，母液在释放曲马多碱后，可以再用于外消旋体的分离过程。
实施例1
盐酸(-)-(1S，2S)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇(-1)
第一步：释放外消旋碱
将3kg(10mole)盐酸(1RS，2RS)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇(1)悬浮于4800ml水中，并用1.6kg碎冰处理。边搅拌边滴加1300ml 36-38％(工业级)苛性苏打溶液。随后混合物用7000ml二氯甲烷提取，在相分离后再用2000ml二氯甲烷提取。合并的有机相通过硫酸钠干燥。通过蒸馏除去溶剂后，得到2630g(理论值的99％)(1RS，2RS)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇的糖浆。
第二步：用L-(+)-酒石酸沉淀
将第一步得到的2630g(10mole)碱溶于2400ml乙醇中，用由1500g(10mole)L-(+)-酒石酸和11,200ml乙醇组成的溶液处理。混合物在室温下搅拌2小时，并在4℃放置24小时进行结晶。沉淀的结晶经过抽滤，在4℃用6400ml乙醇洗涤。结晶物在室温下真空(60mbar)干燥后，得到2050g(使用的外消旋碱总量的49％)熔点为173-175℃的L-(+)-酒石酸(1S，2S)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇(比旋：[α]RT D＝-12.2°(c＝1.01；甲醇))。
第三步：从L-(+)-酒石酸盐中释放碱
将第二步得到的2050g(4.95mole)L-(+)-酒石酸(1S，2S)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇溶于4000ml水中，用900g碎冰处理。边搅拌边滴加1000ml 36-38％(工业级)苛性苏打溶液。随后混合物用2500ml二氯甲烷提取，在相分离后再用500ml二氯甲烷提取。合并的有机相用硫酸钠干燥。通过蒸馏除去溶剂后，得到1280g(理论值的99％)(1S，2S)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇的糖浆。
第四步：将(1S，2S)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇转化为盐酸盐(-1)
第三步得到的1280g(4.86mole)碱溶于1612-丁酮中，边搅拌边用88ml(4.9mole)水和621ml(532g；4.9mole)三甲氯硅烷处理。混合物在室温下搅拌3小时，并在4℃放置24小时进行结晶。沉淀的固体经过抽滤，在4℃用5000ml 2-丁酮洗涤，在90℃真空(60mbar)干燥至恒重。得到1390g(相对于第三步使用的碱的理论值的95％，相对于第一步使用的外消旋体对映体含量的理论值的92％)盐酸盐(-1)的无色晶体。
熔点：172-173℃
比旋：[α]RT D＝-29.6°(c＝1.00；甲醇)。
实施例2
盐酸(+)-(1R，2R)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇(+1)
第一步：从L-(+)-酒石酸沉淀的母液中释放碱
合并来自L-(+)-酒石酸沉淀(实施例1，第二步)的乙醇母液和洗涤相。通过蒸馏除去溶剂后，将残留物(2080g)溶于2500ml水中，用900g碎冰处理。边搅拌边滴加1000ml 36-38％(工业级)苛性苏打溶液。随后混合物用2700ml二氯甲烷提取，在相分离后再用600ml的二氯甲烷提取。合并的有机相用硫酸钠干燥。通过蒸馏除去溶剂后，得到1340g(理论值的99％)(1R，2R)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇的糖浆。
第二步：将(1R，2R)-2-二甲氨基甲基-1-(3-甲氧基苯基)-环己醇转化为盐酸盐(+1)
第一步得到的1340g(5.09mole)碱溶于17.51 2-丁酮中，边搅拌边用105ml(5.8mole)水和670ml(573g；5.3mole)三甲氯硅烷处理。混合物在室温下搅拌3小时，并在该温度放置24小时进行结晶。沉淀的固体经过抽滤，用5000ml 2-丁酮洗涤，在90℃真空(60mbar)干燥为恒重。得到1350g(目对于第一步使用的碱的理论值的88％，相对于实施例1第一步使用的外消旋体对映体含量的理论值的89％)盐酸盐(+1)的无色晶体。
熔点：171-172℃
比旋：[α]RT D＝+29.6°(c＝1.00；甲醇)。
Claims (5)
1.一种分离曲马多外消旋体的方法，其特征在于，将外消旋的曲马多盐转化为碱，用L-(+)-酒石酸处理碱，通过沉淀来分离(-)-曲马多对映体的L-(+)-酒石酸盐，而通过释放曲马多碱，然后再转化为不同于酒石酸盐的盐，从其以L-(+)酒石酸盐的形式溶于其中的母液中分离(+)-曲马多对映体。
2.按照权利要求1的方法，其特征在于，使用外消旋的盐酸曲马多。
3.按照权利要求1或2的方法，其特征在于，在脂族C1-5醇的存在下使用L-(+)-酒石酸。
4.按照权利要求1或2的方法，其特征在于，通过结晶分离(-)-曲马多对映体的L-(+)-酒石酸盐。
5.按照权利1或2的方法，其特征在于，(-)-曲马多对映体和(+)-曲马多对映体以盐酸盐的形式分离。
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| DE19601745.9 | 1996-01-19 | ||
| DE19601745A DE19601745C1 (de) | 1996-01-19 | 1996-01-19 | Verfahren zur Racematspaltung von Tramadol |
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| ES2130079B1 (es) * | 1997-07-10 | 2000-01-16 | Esteve Labor Dr | Resolucion de aminas |
| DK0996613T3 (da) * | 1997-07-15 | 2003-03-03 | Russinsky Ltd | Fremstilling af rent cis-tramadol-hydrochlorid |
| DE19821039A1 (de) | 1998-05-11 | 1999-11-18 | Bayer Ag | Verfahren zur Herstellung von (S,S)-Benzyl-2,8-diazabicyclo[4.3.0]nonan |
| GB9826540D0 (en) | 1998-12-02 | 1999-01-27 | Darwin Discovery Ltd | Process |
| KR100342919B1 (ko) * | 1999-10-21 | 2002-07-04 | 박노중 | 트랜스체 염산 트라마돌의 분리 제조방법 |
| AU2001294979B2 (en) * | 2000-10-03 | 2007-03-29 | Penwest Pharmaceuticals Company | Delivery system for multi-pharmaceutical active materials at various release rates |
| DE10108122A1 (de) | 2001-02-21 | 2002-10-02 | Gruenenthal Gmbh | Arzneimittel auf Basis von Tramadol |
| CN1289071C (zh) | 2001-03-16 | 2006-12-13 | Dmi生物科学公司 | 曲马朵物质在制备用于延缓男性射精的药物中的用途 |
| US6649783B2 (en) * | 2001-10-03 | 2003-11-18 | Euro-Celtique, S.A. | Synthesis of (+/-)-2-((dimethylamino)methyl)-1-(aryl)cyclohexanols |
| US6780891B2 (en) | 2001-11-30 | 2004-08-24 | Sepracor Inc. | Tramadol analogs and uses thereof |
| US20040248979A1 (en) * | 2003-06-03 | 2004-12-09 | Dynogen Pharmaceuticals, Inc. | Method of treating lower urinary tract disorders |
| WO2006081276A1 (en) | 2005-01-26 | 2006-08-03 | Allergan, Inc. | 3-heteroaryl-3-hydroxy-2-amino-propyl amines and related compounds having analgesic and/or immuno stimulant activity |
| EP1785412A1 (en) * | 2005-11-14 | 2007-05-16 | IPCA Laboratories Limited | Tramadol recovery process |
| WO2008100926A1 (en) * | 2007-02-12 | 2008-08-21 | Dmi Biosciences, Inc. | Treatment of comorbid premature ejaculation and erectile dysfunction |
| BRPI0807281A2 (pt) * | 2007-02-12 | 2014-04-29 | Dmi Biosciences Inc | Reduzindo os efeitos colaterais de tramadol |
| DE102013009114A1 (de) | 2013-05-29 | 2014-12-04 | Franz Gerstheimer | Pharmazeutische Zusammensetzung zur Überwindung von Metabolisierungsproblemen |
| KR102136004B1 (ko) | 2018-06-18 | 2020-07-22 | (주)센텍코리아 | 감지부의 잔존 수명을 추정할 수 있는 음주측정기 |
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| IL50080A (en) * | 1975-07-29 | 1979-07-25 | Beecham Group Ltd | 4-oxa-1-azabicyclo(3.2.0)heptan-7-one-2-car boxylic acid derivatives and their preparation |
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