KR20010113799A - 신규한 방법 - Google Patents
신규한 방법 Download PDFInfo
- Publication number
- KR20010113799A KR20010113799A KR1020017013069A KR20017013069A KR20010113799A KR 20010113799 A KR20010113799 A KR 20010113799A KR 1020017013069 A KR1020017013069 A KR 1020017013069A KR 20017013069 A KR20017013069 A KR 20017013069A KR 20010113799 A KR20010113799 A KR 20010113799A
- Authority
- KR
- South Korea
- Prior art keywords
- formula
- compound
- acid
- hexamethyldisilazide
- phenyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 11
- FWUQWDCOOWEXRY-ZDUSSCGKSA-N lanicemine Chemical compound C([C@H](N)C=1C=CC=CC=1)C1=CC=CC=N1 FWUQWDCOOWEXRY-ZDUSSCGKSA-N 0.000 claims description 8
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical group [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 8
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 claims description 5
- 229910052751 metal Inorganic materials 0.000 claims description 5
- 239000002184 metal Substances 0.000 claims description 5
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical group C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 3
- 125000004076 pyridyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- DZAIOXUZHHTJKN-UHFFFAOYSA-N 2-Desoxy-D-glycero-tetronsaeure Natural products OCC(O)CC(O)=O DZAIOXUZHHTJKN-UHFFFAOYSA-N 0.000 description 1
- NMWDYLYNWRFEMR-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1.CC1=CC=CC=N1 NMWDYLYNWRFEMR-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 229940099433 NMDA receptor antagonist Drugs 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 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 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000001273 butane Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Abstract
본 발명은 특정의 제약학상 활성인 피리딜 화합물을 제조하는 신규 방법에 관한 것이다.
Description
본 발명은 특정 의약제의 개선된 제조 방법에 관한 것이다.
EP 0 633 879 B1에는 NMDA 수용체 길항제 활성을 갖는 것으로 알려진 화합물이 기재되어 있다. (S)-1-페닐-2-(2-피리딜)에탄아민으로 알려진 화합물이 특히 졸중의 치료용으로서 특히 관심을 끌고 있다. 그러나, EP 0 633 879 B1에 기재된 이 화합물의 제조 방법은, 예컨대 대규모에서 사용하기에는 용이하지 않은 부틸리튬을 사용해야 하는 등 몇 가지 불리한 특성으로 인해 좋지 않다.
본 발명에 이르러, 부틸리튬을 사용할 필요가 없어 상업적으로 이용하기에 보다 적합한, (S)-1-페닐-2-(2-피리딜)에탄아민을 제조하기 위한 신규 방법이 개발되었다. 본 발명의 방법은 부틸리튬을 사용할 필요가 없기 때문에, 부탄의 방출에 수반되는 환경 문제를 피할 수 있다는 추가의 이점을 갖는다. 또한, 놀랍게도 본 발명의 방법은 EP 0 633 879 B1에서와 같이 염기를 화학량론적 양으로 사용하지 않고 염기를 (화학식 II의 2-피콜린에 대해) 촉매량만 사용하고서도 행할 수 있다. 따라서, 청구하는 모든 방법은 EP 0 633 879 B1의 것보다 더 효과적이고, 안전하며, 보다 환경 친화적일 뿐만 아니라 저렴하다.
따라서, 본 발명의 제1 측면은 금속 헥사메틸디실라지드의 존재하에 하기 화학식 II의 화합물을 하기 화학식 III의 화합물과 반응시키고, 이후에 임의로 화학식 I의 화합물의 에난티오머를 분할하여 제약학상 허용 가능한 염을 형성시키는 것을 포함하는, 하기 화학식 I의 화합물 또는 그의 제약학상 허용 가능한 염의 제조 방법을 제공하는 것이다.
화학식 III의 화합물은 벤즈알데히드 및 금속 헥사메틸디실라지드, 바람직하게는 리튬 헥사메틸디실라지드(LHMDS)로부터 제조할 수 있다. 화학식 III의 화합물은 감온, 즉 35℃ 미만, 바람직하게는 25℃ 미만에서 제조하는 것이 바람직하다.
화학식 II의 화합물과 화학식 III의 화합물의 반응은 승온, 예를 들어 약 40℃에서 행하는 것이 적합하다. 반응은 불활성 용매, 바람직하게는 t-부틸 메틸 에테르와 같은 에테르성 용매, 보다 바람직하게는 테트라히드로푸란에서 행한다. 바람직한 금속 헥사메틸디실라지드는 리튬 헥사메틸디실라지드(LHMDS)이고, 이 염기는 화학식 II의 2-피콜린 (2-메틸피리딘)에 대해 촉매량, 예를 들어 약 10 몰%로 사용한다. 반응 혼합물을 산성 후처리함으로써 필요한 화학식 I의 화합물을 얻는다.
본 발명의 화합물은 제약학상 허용 가능한 용매화물 및 염을 형성할 수 있다. 화학식 I의 화합물은 산, 예컨대 통상적으로 제약학상 허용 가능한 산, 예를 들어 말산, 염산, 브롬화수소산, 인산, 아세트산, 푸마르산, 살리실산, 시트르산, 락트산, 만델산, 타르타르산, 트리플루오로아세트산 및 메탄술폰산과 산부가염을 형성할 수 있다. 바람직한 염은 말레에이트 및 히드로클로라이드 염이다.
특히 바람직한 염은 키랄산을 사용하여 EP 0 691 957 B1에 기재된 바와 같은 화학식 I의 단독 에난티오머의 염을 제조할 수 있는 것이다. 화학식 I의 라세미체 화합물을 (S)-말산으로 처리하여 (S)-1-페닐-2-(2-피리딜)에탄아민 (S)-말레에이트를 얻는 것이 바람직하다.
본 발명의 추가의 측면은 본 명세서에 기재된 방법을 이용하여 제조된 (S)-1-페닐-2-(2-피리딜)에탄아민 및 그의 염, 특히 (S)-말레에이트 염을 제공하는 것이다.
본 발명을 하기 실시예로 예시한다.
(S)-α-페닐-2-피리딘에탄아민 (S)-말레에이트
리튬 헥사메틸디실라지드의 용액 (테트라히드로푸란 중의 1.0 M 용액 1100mL, 1.1 mol)을 질소하에서 냉각시켜 온도를 25℃ 미만으로 유지하면서 테트라히드로푸란 (305 ml) 중의 벤즈알데히드 (102 ml, 1.0 mol)의 교반한 용액에 적가하였다. 얻어진 용액을 20℃에서 30 분 동안 교반하고, 2-피콜린 (101 ml, 1.0 mol)을 한 번에 가한 후, 추가의 테트라히드로푸란 (102 ml)을 가하였다. 이어서, 반응 혼합물을 30 분에 걸쳐서 40℃로 가열한 후, 40℃에서 90 분 동안 유지하였다. 그 후, 용액을 10 분에 걸쳐 20℃로 냉각시키고, 10 내지 20℃의 온도를 유지하도록 냉각시키면서 탈-미네랄수 (900 ml) 중의 진한 염산 (420 ml, 5.0 mol) 용액에 적가하였다. 얻어진 혼합물 (pH 1)을 20℃에서 15 분 동안 교반한 후, 층을 분리시켰다. 아래 쪽의 수상을 분리하고, 에틸 아세테이트 (2 ×900 ml)로 세척한 후, 10 내지 20℃의 온도를 유지하도록 냉각시키면서 탈-미네랄수 (830 ml) 중의 수산화나트륨 (200 g, 5.0 mol)의 용액을 가하여 염기성화시켰다. 얻어진 혼합물 (pH 12)을 20℃에서 15 분 동안 교반한 후, 에틸 아세테이트 (2 ×800 ml)로 추출하였다. 이어서, 에틸 아세테이트 용액을 에탄올 (1060 ml) 중의 S-말산 (120.7 g, 0.9 mol)의 용액에 가한 후, 표제 화합물의 결정핵 (0.2 g)을 가하였다. 이 혼합물을 20℃에서 30 분 동안 교반한 후, 0℃로 냉각시키고 0℃에서 20 시간 동안 교반하였다. 현탁액을 여과하고, 에탄올 (530 ml)로 세척하여 백색 고상물을 얻고, 이것을 40℃의 진공에서 밤새 건조시켜 공지된 물질과 동일한 (S)-α-페닐-2-피리딘에탄아민 (S)-말레에이트 (119.07 g, 35.8%)를 백색 고상물로 수득하였다.
Claims (7)
- 금속 헥사메틸디실라지드의 존재하에 하기 화학식 II의 화합물을 하기 화학식 III의 화합물과 반응시키고, 이후에 임의로 화학식 I의 화합물의 에난티오머를 분할하여 제약학상 허용 가능한 염을 형성시키는 것을 포함하는, 하기 화학식 I의 화합물 또는 그의 제약학상 허용 가능한 염의 제조 방법.<화학식 I><화학식 II><화학식 III>
- 제1항에 있어서, 금속 헥사메틸디실라지드가 리튬 헥사메틸디실라지드인 방법.
- 제1항 또는 제2항에 있어서, 화학식 II 및 III의 화합물을 에테르성 용매 중에서 반응시키는 방법.
- 제1항 내지 제3항 중 어느 한 항에 있어서, 리튬 헥사메틸디실라지드를 화학식 II의 화합물에 대해 촉매량으로 사용하는 방법.
- 제1항 내지 제4항 중 어느 한 항에 있어서, 화학식 II의 화합물 대 리튬 헥사메틸디실라지드의 몰비가 약 10:1인 방법.
- 제1항 내지 제5항 중 어느 한 항에 따른 방법에 따라 제조된 (S)-1-페닐-2-(2-피리딜)에탄아민 또는 그의 염.
- 제1항 내지 제5항 중 어느 한 항에 따른 방법에 따라 제조된 (S)-1-페닐-2-(2-피리딜)에탄아민 (S)-말레에이트 염.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9901340A SE9901340D0 (sv) | 1999-04-15 | 1999-04-15 | Novel process |
| SE9901340-1 | 1999-04-15 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20010113799A true KR20010113799A (ko) | 2001-12-28 |
| KR100663811B1 KR100663811B1 (ko) | 2007-01-03 |
Family
ID=20415222
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020017013069A KR100663811B1 (ko) | 1999-04-15 | 2000-04-14 | 신규한 방법 |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US6518432B1 (ko) |
| EP (1) | EP1492769B1 (ko) |
| JP (1) | JP4676064B2 (ko) |
| KR (1) | KR100663811B1 (ko) |
| CN (1) | CN1138759C (ko) |
| AT (1) | ATE333444T1 (ko) |
| AU (1) | AU773962B2 (ko) |
| BR (1) | BR0009795B1 (ko) |
| CA (1) | CA2367410C (ko) |
| DE (1) | DE60029493T2 (ko) |
| ES (1) | ES2267526T3 (ko) |
| IL (2) | IL145585A0 (ko) |
| NO (1) | NO320810B1 (ko) |
| NZ (1) | NZ514586A (ko) |
| SE (1) | SE9901340D0 (ko) |
| TW (1) | TWI248433B (ko) |
| WO (1) | WO2000063175A2 (ko) |
| ZA (1) | ZA200108374B (ko) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MX2011006680A (es) * | 2008-12-24 | 2011-07-12 | Astrazeneca Ab | Compuestos etanaminicos y su uso para tratar la depresion. |
| TR201909632T4 (tr) | 2013-11-05 | 2019-07-22 | Astrazeneca Ab | Nmda antagonisti ön ilaçları. |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9320273D0 (en) * | 1993-04-01 | 1993-11-17 | Fisons Corp | Compound useful in therapy |
| US5455259A (en) * | 1987-02-06 | 1995-10-03 | Fisons Corporation | Compounds for the treatment of neurodegenerative disorders |
| EP0540318A1 (en) * | 1991-10-30 | 1993-05-05 | Fisons Corporation | 2-Heterocyclicethylamine derivatives and their use as pharmaceuticals |
| SG47948A1 (en) | 1992-04-03 | 1998-04-17 | Astra Ab | Compounds for the treatment of neurodegenerative disorders |
-
1999
- 1999-04-15 SE SE9901340A patent/SE9901340D0/xx unknown
-
2000
- 2000-04-05 TW TW089106214A patent/TWI248433B/zh not_active IP Right Cessation
- 2000-04-14 JP JP2000612269A patent/JP4676064B2/ja not_active Expired - Fee Related
- 2000-04-14 IL IL14558500A patent/IL145585A0/xx active IP Right Grant
- 2000-04-14 DE DE60029493T patent/DE60029493T2/de not_active Expired - Lifetime
- 2000-04-14 NZ NZ514586A patent/NZ514586A/en not_active IP Right Cessation
- 2000-04-14 BR BRPI0009795-0A patent/BR0009795B1/pt not_active IP Right Cessation
- 2000-04-14 EP EP00925816A patent/EP1492769B1/en not_active Expired - Lifetime
- 2000-04-14 CN CNB00806198XA patent/CN1138759C/zh not_active Expired - Fee Related
- 2000-04-14 ES ES00925816T patent/ES2267526T3/es not_active Expired - Lifetime
- 2000-04-14 AU AU44447/00A patent/AU773962B2/en not_active Ceased
- 2000-04-14 CA CA002367410A patent/CA2367410C/en not_active Expired - Fee Related
- 2000-04-14 AT AT00925816T patent/ATE333444T1/de not_active IP Right Cessation
- 2000-04-14 WO PCT/SE2000/000713 patent/WO2000063175A2/en active IP Right Grant
- 2000-04-14 KR KR1020017013069A patent/KR100663811B1/ko not_active IP Right Cessation
- 2000-04-14 US US09/555,050 patent/US6518432B1/en not_active Expired - Lifetime
-
2001
- 2001-09-24 IL IL145585A patent/IL145585A/en not_active IP Right Cessation
- 2001-10-08 NO NO20014889A patent/NO320810B1/no not_active IP Right Cessation
- 2001-10-11 ZA ZA200108374A patent/ZA200108374B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU4444700A (en) | 2000-11-02 |
| ES2267526T3 (es) | 2007-03-16 |
| CN1370145A (zh) | 2002-09-18 |
| ATE333444T1 (de) | 2006-08-15 |
| DE60029493T2 (de) | 2007-01-11 |
| NO20014889L (no) | 2001-10-08 |
| ZA200108374B (en) | 2003-08-06 |
| SE9901340D0 (sv) | 1999-04-15 |
| IL145585A (en) | 2006-12-31 |
| EP1492769B1 (en) | 2006-07-19 |
| WO2000063175A2 (en) | 2000-10-26 |
| DE60029493D1 (de) | 2006-08-31 |
| KR100663811B1 (ko) | 2007-01-03 |
| AU773962B2 (en) | 2004-06-10 |
| US6518432B1 (en) | 2003-02-11 |
| BR0009795A (pt) | 2002-01-08 |
| JP2003524625A (ja) | 2003-08-19 |
| TWI248433B (en) | 2006-02-01 |
| EP1492769A2 (en) | 2005-01-05 |
| WO2000063175A3 (en) | 2004-11-11 |
| CA2367410C (en) | 2009-08-11 |
| JP4676064B2 (ja) | 2011-04-27 |
| BR0009795B1 (pt) | 2011-12-27 |
| NO320810B1 (no) | 2006-01-30 |
| CN1138759C (zh) | 2004-02-18 |
| CA2367410A1 (en) | 2000-10-26 |
| NO20014889D0 (no) | 2001-10-08 |
| NZ514586A (en) | 2003-09-26 |
| IL145585A0 (en) | 2002-11-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP7085641B2 (ja) | アルコラート塩基の存在下でのニコチン酸エチルとｎ－ビニルピロリドンとの反応によるラセミ体ニコチンの調製方法 | |
| US9440959B2 (en) | Process for the preparation of nilotinib | |
| IE65378B1 (en) | Piperazine derivatives | |
| JPH04264078A (ja) | ピペラジン誘導体の製造方法 | |
| US7709677B2 (en) | Process of preparing arylethanoldiamines | |
| KR100663811B1 (ko) | 신규한 방법 | |
| JPH08502738A (ja) | アミド誘導体 | |
| CN109810052B (zh) | 一种高选择性的阿帕替尼的简便制备方法 | |
| NO781618L (no) | Fremgangsmaate ved fremstilling av nye chromenderivater | |
| JPH05202054A (ja) | アミノメチル置換２，３−ジヒドロピラノ〔２，３−ｂ〕ピリジン類 | |
| JP4140066B2 (ja) | 場合により２−置換されている５−クロロイミダゾール−４−カルボアルデヒドの製造方法 | |
| MXPA01010129A (es) | Proceso novedoso para la preparacion de ciertos compuestos de piridilo | |
| US4091103A (en) | Quinolyl or isoquinolyl-lower-alkoxy-phenylene-amino derivatives | |
| EP4186890A1 (en) | Preparation of n-benzyl-2-(5-bromo-pyridin-2-yl)-acetamide for the synthesis of tirbanibulin | |
| JP2001500881A (ja) | アルコール置換フェノール化合物の選択アルキル化 | |
| JPH053858B2 (ko) | ||
| IL142760A (en) | Method for producing 4-Ä(2',5'-diamino-6'- halopyrimidine-4' -yl) aminoÜ-cyclopent -2- enyl-methanols | |
| WO2007035003A1 (ja) | 光学活性なピペラジン化合物の製造方法 | |
| JPH08503939A (ja) | α−アリール‐γ‐ブチロラクトンの製造方法 | |
| JPH10231288A (ja) | ２−クロロ−４−アミノメチルピリジンの製造方法 | |
| JP2001064265A (ja) | アルキルヒダントイン類 | |
| JP5080050B2 (ja) | 光学活性なピペラジン化合物の製造方法 | |
| JP2003507463A (ja) | 置換ピペラジン誘導体、その調製及びその薬物としての使用 | |
| JP2006524196A (ja) | ニコチンアルデヒドの製造方法。 | |
| WO2000063174A1 (en) | Novel process |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20121130 Year of fee payment: 7 |
|
| FPAY | Annual fee payment |
Payment date: 20131129 Year of fee payment: 8 |
|
| FPAY | Annual fee payment |
Payment date: 20141201 Year of fee payment: 9 |
|
| FPAY | Annual fee payment |
Payment date: 20151201 Year of fee payment: 10 |
|
| LAPS | Lapse due to unpaid annual fee |