TWI248433B - Process for the preparation of pyridyl ethanamine derivatives - Google Patents
Process for the preparation of pyridyl ethanamine derivatives Download PDFInfo
- Publication number
- TWI248433B TWI248433B TW089106214A TW89106214A TWI248433B TW I248433 B TWI248433 B TW I248433B TW 089106214 A TW089106214 A TW 089106214A TW 89106214 A TW89106214 A TW 89106214A TW I248433 B TWI248433 B TW I248433B
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- Taiwan
- Prior art keywords
- compound
- formula
- patent application
- preparation
- pharmaceutically acceptable
- Prior art date
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- 238000000034 method Methods 0.000 title claims abstract description 15
- -1 pyridyl ethanamine derivatives Chemical class 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 27
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 2
- 229910052744 lithium Inorganic materials 0.000 claims 2
- JEBPUSJPDDISRP-UHFFFAOYSA-N 1,6-diazidohexane Chemical compound [N-]=[N+]=NCCCCCCN=[N+]=[N-] JEBPUSJPDDISRP-UHFFFAOYSA-N 0.000 claims 1
- 229910052751 metal Inorganic materials 0.000 abstract description 5
- 239000002184 metal Substances 0.000 abstract description 5
- XGIUDIMNNMKGDE-UHFFFAOYSA-N bis(trimethylsilyl)azanide Chemical compound C[Si](C)(C)[N-][Si](C)(C)C XGIUDIMNNMKGDE-UHFFFAOYSA-N 0.000 abstract 2
- 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 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 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
- 239000000243 solution Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 150000001540 azides Chemical class 0.000 description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-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
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- 239000000203 mixture Substances 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
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-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
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- FWUQWDCOOWEXRY-ZDUSSCGKSA-N lanicemine Chemical compound C([C@H](N)C=1C=CC=CC=1)C1=CC=CC=N1 FWUQWDCOOWEXRY-ZDUSSCGKSA-N 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 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
- BSKHPKMHTQYZBB-UHFFFAOYSA-O 2-methylpyridin-1-ium Chemical compound CC1=CC=CC=[NH+]1 BSKHPKMHTQYZBB-UHFFFAOYSA-O 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
- 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
- PQBAWAQIRZIWIV-UHFFFAOYSA-N N-methylpyridinium Chemical compound C[N+]1=CC=CC=C1 PQBAWAQIRZIWIV-UHFFFAOYSA-N 0.000 description 1
- 241000221035 Santalaceae Species 0.000 description 1
- 235000008632 Santalum album Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- ZEOKIADLNMQWMR-UHFFFAOYSA-N [N-]=[N+]=[N-].[Li+].C(CCCCCF)F Chemical compound [N-]=[N+]=[N-].[Li+].C(CCCCCF)F ZEOKIADLNMQWMR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 238000000605 extraction Methods 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
- GUWHRJQTTVADPB-UHFFFAOYSA-N lithium azide Chemical compound [Li+].[N-]=[N+]=[N-] GUWHRJQTTVADPB-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 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
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 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
Classifications
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- 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)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hematology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Epidemiology (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Catalysts (AREA)
Description
1248433 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明（1 ) 本發明係有關於一種製備某些藥劑之改良方法。 EP 0 633 879 B1揭露具受體拮抗劑活性之化合 物。稱爲（S)_l-苯基_2_(2_吡啶基）乙胺之化合物特別爲人 所關注’尤其是用於治療中風。然而，揭露於 EP 0 6；33 879 B1之製備該化合物方法遭遇到某些缺點。如 需利用不便大量使用之丁基鐘。 現已發展出一種新穎製備（s)el_苯基_2_(2_吡啶基）乙胺方 法，其可避免使用丁基鋰之需要且因而更適合商業用途。 由於本發明方法毋須使用丁基鋰，因此亦具有額外優點， 即其將避免丁 散發相關之環保問題。更進一步，令人驚 冴地發現本方法僅需催化劑量之鹼[有關於式（〗〗）之甲 基吡哫]即可進行，而非如於Ep 〇 633 879 B1中所使用之 化學劑量之驗。故整體而言本專利申請之方法較 ep〇 633 879 B1更有效、更安全、更環保且更便宜。 本發明I首要觀點係提供一種製備式化合物或其醫 藥學可接受鹽類之方法：
其包括： 將式（11)化合物： α ⑼ N ch3 --------訂—-------- (請先間讀背面之注意事項再填寫本頁) 本纸張尺度適用中國國家標準（C]NTS)A4規格（21〇 297公釐） 1248433 A7 -----------B7_ 五、發明說明（2 ) 與式（ΠΙ)化合物反應： zSiMeq N 3
(III) I於金屬六甲基二矽疊氮化物存在的情況下進行）並視需要 醚後/合解式（I)化合物對映體並形成醫藥學可接受鹽類。 式（III)化合物可由苯甲醛及金屬六甲基二矽疊氮化物 (較佳爲六甲基二矽疊氮化鋰（LHMDS))製備。式（III)化 合物較佳於低溫製備，即低於35〇c，較佳爲低於25。〇。 化合物（II)及（III)反應適於較高溫進行，如約4〇。〇。反 應可於惰性溶劑中進行，較佳於醚溶劑進行，如t_丁基甲 醚或更佳爲四氫呋喃。較佳之金屬六甲基二矽疊氮化物爲 六甲基二矽疊氮化鋰（LHMDS)且該鹼對式（11) 2_甲基吡 哫使用時爲催化劑量，如約i 〇莫耳百分比。反應混合物 之酸性分離物可產生所需之式（〗）化合物。 經濟部智慧財產局員工消費合作社印製 本發明化合物可形成醫藥學可接受溶劑化物及鹽類。式 (I)化合物可與酸形成酸性附加鹽，如慣用醫藥學可接受 之酸，如羥基丁二酸、鹽酸、氫溴酸、磷酸、醋酸、反丁 烯一酸、水揚酸、檸檬酸、乳酸、苯甲醇酸、酒石酸、三 氟醋酸及甲磺酸。較佳鹽類爲羥基丁二酸鹽.及鹽酸鹽。 特佳之鹽類可使用手性酸製備以獲得如揭露於 EP 0 691 957 B1之化合物（！）的單一對映體之鹽 -5- A7 1248433 五、發明說明（3 佳爲以（S)-羥基丁二酸處理式（I)之外消旋物化合物以獲得 (S)-l-苯基-2-(2-p比咬基）乙胺（S)-#l基丁二酸鹽。 本發明更進一步之觀點係提供依據在此所述方法製備之 (S)-l-苯基-2-(2-吡啶基）乙胺及其鹽類，特定言之爲（s)户 基丁二酸鹽。 本發明以下列實例説明。 實例 (S)- α -笨某-2-p比淀乙胺基丁二酸鹽 將六曱基二矽疊氮化鋰溶液（11〇〇毫升之1〇Μ四氫唉喃 溶液，1 · 1莫耳）於氮氣中、冷卻下滴入至攪拌中的含苯甲 醛（102毫升，1.0莫耳）之四氫呋喃（3〇5毫升）溶液中，溫 度維持25 °C以下。將所產生溶液於2〇 X：下攪拌3 〇分鐘 後’添加一份2 -甲基吡啶（1 〇 1毫升，1 〇莫耳），再加入 四氫吱喃（1 0 2毫升）。以3 0分鐘以上的時間將反應混合物 再加熱至40°C，並維持40°C達9 0分鐘。再以i 〇分鐘以上 的時間將該溶液冷卻至2〇°C，並滴至含濃縮鹽酸（4 2 〇毫 升，5.0莫耳）之去礦物質水（9 〇 〇毫升）溶液中，同時冷卻 舲溫度維持於i 0至20。〇間。將所產生混合物（pH〗）於2〇 C檀拌1 5分鐘後分層。將較低之水相分離出並以醋酸乙 醋（2 X 900毫升）沖洗，再藉添加含氫氧化鈉（2〇〇克，5〇 莫耳）之去礦物質水（8 3 0毫升）溶液將其鹼化，同時冷卻 維持溫度範圍於丨〇至20°C間。產生之混合物（pH 12)於2〇 C I拌1 5分鐘，再以醋酸乙酯（2 χ 8〇〇毫升）萃取。再將 醋酸乙醋溶液加至含S_羥基丁二酸（12〇.7克，〇 9莫耳）之 -6 - 規格（210 x 297公爱） --------訂·-------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 1248433
、發明說明（ 乙醇（1060毫升）溶液中，再添力口標題化合物之晶種（〇 2 克）。該混合物於2(TC攪摔3 0分鐘^再冷卻至〇Ό且於〇°C 攪拌2 0小時。將懸浮液過濾並以乙醇（5 3 〇毫升）沖洗而獲 得白色固體，再於4(TC眞空烘箱乾燥過夜以獲得與已知物 質相同之（S)-a-苯基-2-吡啶乙胺（S)_羥基丁二酸鹽（ι19 〇7 克，35.8%)白色固體。 1^ n .n 1^1 «In ϋ ϋ n · 1 n· ϋ I I i t I 1 a n n I I (請先閱括-M背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本纸張&度適用中國國家標準（CNS)A4規格（210 x 297公爱） 申請曰期 案 號 _〇^〇6214_ 類 別 1248433 f I f vi A 4 1 C4 中文說明書修正頁（91年9月） 發明新^專利説明書
中 文 製備1^比咬基乙胺衍生物之方法 明 名稱 英 文 姓 名 ^PROCESS FOR THE PREPARATION OF PYRIDYL ETHANAMINE DERIVATIVES, 梅爾文蓋爾斯 國 籍 英國 住、居所 姓 名 (名稱? 國 籍 英國萊斯市勞伯洛區貝克威路阿斯特捷利康查伍廠 英商阿斯特捷利康英國股份有限公司 英國 裝 訂 i 中請人 (事為^ 英國倫敦市史丹霍普路15號 琳達梅史拉克
本紙張尺度通 中國國豕榡準(CNS) A4規格(210 X 297公釐)
Claims (1)
- A B c D 12484$3)89106214號專利申請案 中文申請專利範圍修正本（91年9月) 申請專利範圍 1. 一種製備式（I)化合物或其醫藥上可接受鹽類之方法⑴ 其包括： 於六甲基二矽疊氮化鋰存在下，令式（II)化合物CH, (II) 與式（III)化合物： Η fvT .SiMe,(HI) 反應，並於爾後視需要溶解式（I)化合物對映體而形成 一醫藥上可接受鹽類， 其中相對於式（11)化合物係使用一催化劑量之六曱基 二矽疊氮化鋰。 2.如申請專利範圍第1項之方法，其中之化合物（11)及 (III)係於醚溶劑中反應。 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 8 8 8 8 A B c D 1248433 、申請專利範圍 3.如申請專利範圍第1項之方法，其中化合物（11)相對 甲基二矽疊氮化鋰之莫耳比例約為10 : 1。 -2 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐）
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9901340A SE9901340D0 (sv) | 1999-04-15 | 1999-04-15 | Novel process |
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| US (1) | US6518432B1 (zh) |
| EP (1) | EP1492769B1 (zh) |
| JP (1) | JP4676064B2 (zh) |
| KR (1) | KR100663811B1 (zh) |
| CN (1) | CN1138759C (zh) |
| AT (1) | ATE333444T1 (zh) |
| AU (1) | AU773962B2 (zh) |
| BR (1) | BR0009795B1 (zh) |
| CA (1) | CA2367410C (zh) |
| DE (1) | DE60029493T2 (zh) |
| ES (1) | ES2267526T3 (zh) |
| IL (2) | IL145585A0 (zh) |
| NO (1) | NO320810B1 (zh) |
| NZ (1) | NZ514586A (zh) |
| SE (1) | SE9901340D0 (zh) |
| TW (1) | TWI248433B (zh) |
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| ZA (1) | ZA200108374B (zh) |
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| NZ593282A (en) | 2008-12-24 | 2013-06-28 | Astrazeneca Ab | Ethanamine compounds and their use for treating depression |
| JP6479834B2 (ja) | 2013-11-05 | 2019-03-06 | アストラゼネカ・アクチエボラーグＡｓｔｒａｚｅｎｅｃａ Ａｋｔｉｅｂｏｌａｇ | Ｎｍｄａアンタゴニストプロドラッグ |
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| 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 |
| WO1993020052A1 (en) | 1992-04-03 | 1993-10-14 | Fisons Corporation | Enantiomeric 1-phenyl-2-(2-pyridinyl)ethylamine for the treatment of neurodegenerative disorders |
| DK0612314T3 (da) * | 1991-10-30 | 2000-05-29 | Astra Ab | 2-pyrazinylethylaminderivater og deres anvendelse som lægemidler |
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1999
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2000
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| Publication number | Publication date |
|---|---|
| ZA200108374B (en) | 2003-08-06 |
| CA2367410C (en) | 2009-08-11 |
| NO20014889D0 (no) | 2001-10-08 |
| CN1138759C (zh) | 2004-02-18 |
| ATE333444T1 (de) | 2006-08-15 |
| NO320810B1 (no) | 2006-01-30 |
| US6518432B1 (en) | 2003-02-11 |
| CA2367410A1 (en) | 2000-10-26 |
| AU4444700A (en) | 2000-11-02 |
| JP4676064B2 (ja) | 2011-04-27 |
| NO20014889L (no) | 2001-10-08 |
| DE60029493T2 (de) | 2007-01-11 |
| IL145585A (en) | 2006-12-31 |
| DE60029493D1 (de) | 2006-08-31 |
| ES2267526T3 (es) | 2007-03-16 |
| BR0009795A (pt) | 2002-01-08 |
| EP1492769A2 (en) | 2005-01-05 |
| WO2000063175A2 (en) | 2000-10-26 |
| CN1370145A (zh) | 2002-09-18 |
| IL145585A0 (en) | 2002-11-10 |
| BR0009795B1 (pt) | 2011-12-27 |
| WO2000063175A3 (en) | 2004-11-11 |
| KR20010113799A (ko) | 2001-12-28 |
| KR100663811B1 (ko) | 2007-01-03 |
| SE9901340D0 (sv) | 1999-04-15 |
| EP1492769B1 (en) | 2006-07-19 |
| JP2003524625A (ja) | 2003-08-19 |
| NZ514586A (en) | 2003-09-26 |
| AU773962B2 (en) | 2004-06-10 |
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