DK156648B - Fremgangsmaade til fremstilling af 4-methoxy-2'-(2-(1-methyl-2-piperidyl)ethyl)benzanilid (encainid) - Google Patents
Fremgangsmaade til fremstilling af 4-methoxy-2'-(2-(1-methyl-2-piperidyl)ethyl)benzanilid (encainid) Download PDFInfo
- Publication number
- DK156648B DK156648B DK551582A DK551582A DK156648B DK 156648 B DK156648 B DK 156648B DK 551582 A DK551582 A DK 551582A DK 551582 A DK551582 A DK 551582A DK 156648 B DK156648 B DK 156648B
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- DK
- Denmark
- Prior art keywords
- hydrogen
- until
- methyl
- equivalents
- platinum catalyst
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 25
- PJWPNDMDCLXCOM-UHFFFAOYSA-N encainide Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=CC=C1CCC1N(C)CCCC1 PJWPNDMDCLXCOM-UHFFFAOYSA-N 0.000 title description 17
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 21
- 239000003054 catalyst Substances 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 238000005984 hydrogenation reaction Methods 0.000 claims description 10
- 229910052697 platinum Inorganic materials 0.000 claims description 10
- 229960000583 acetic acid Drugs 0.000 claims description 9
- 239000011541 reaction mixture Substances 0.000 claims description 8
- CZDIHHFANHXHCA-UHFFFAOYSA-N 4-methoxy-n-phenyl-2-(2-pyridin-2-ylacetyl)benzamide Chemical compound C=1C=CC=NC=1CC(=O)C1=CC(OC)=CC=C1C(=O)NC1=CC=CC=C1 CZDIHHFANHXHCA-UHFFFAOYSA-N 0.000 claims description 6
- 239000012362 glacial acetic acid Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- -1 1-methyl-2-piperidyl Chemical group 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- BEBIQSRTLZBRRT-UHFFFAOYSA-N lithium;2-methylidenepyridin-1-ide Chemical compound [Li+].[CH2-]C1=CC=CC=N1 BEBIQSRTLZBRRT-UHFFFAOYSA-N 0.000 claims description 3
- 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 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000000543 intermediate Substances 0.000 description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 229960001142 encainide Drugs 0.000 description 15
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 229940102398 methyl anthranilate Drugs 0.000 description 5
- MXMOTZIXVICDSD-UHFFFAOYSA-N anisoyl chloride Chemical compound COC1=CC=C(C(Cl)=O)C=C1 MXMOTZIXVICDSD-UHFFFAOYSA-N 0.000 description 4
- 229940043279 diisopropylamine Drugs 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 239000003416 antiarrhythmic agent Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000001311 chemical methods and process Methods 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- IHMUJQKXSXXRSK-UHFFFAOYSA-N methyl 2-[(4-methoxybenzoyl)amino]benzoate Chemical compound COC(=O)C1=CC=CC=C1NC(=O)C1=CC=C(OC)C=C1 IHMUJQKXSXXRSK-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- MOUYVILUKZKNDE-UHFFFAOYSA-N 2-(2-phenylethyl)piperidine Chemical compound C1CCCNC1CCC1=CC=CC=C1 MOUYVILUKZKNDE-UHFFFAOYSA-N 0.000 description 1
- CMWKITSNTDAEDT-UHFFFAOYSA-N 2-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC=C1C=O CMWKITSNTDAEDT-UHFFFAOYSA-N 0.000 description 1
- AQDSMRFGZNGTOD-UHFFFAOYSA-N 4-methoxy-n-[2-[2-(1-methylpyridin-1-ium-2-yl)ethyl]phenyl]benzamide;methyl sulfate Chemical compound COS([O-])(=O)=O.C1=CC(OC)=CC=C1C(=O)NC1=CC=CC=C1CCC1=CC=CC=[N+]1C AQDSMRFGZNGTOD-UHFFFAOYSA-N 0.000 description 1
- PPQUTVKWIUCDQP-UHFFFAOYSA-N 4-methoxy-n-phenyl-2-(2-pyridin-2-ylacetyl)benzamide;hydrochloride Chemical compound Cl.C=1C=CC=NC=1CC(=O)C1=CC(OC)=CC=C1C(=O)NC1=CC=CC=C1 PPQUTVKWIUCDQP-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910019020 PtO2 Inorganic materials 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001408 amides Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 229940050176 methyl chloride Drugs 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
-
- 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
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- 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
- C07D211/06—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 no double bonds between ring members or between ring members and non-ring members
- C07D211/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
i DK 156648B
Den foreliggende opfindelse angâr en forbedret, mere 0konomisk fremgangsmâde til syntese af encainid (I) -- · CH» % " OCH3 (I) · soin er egnet til fremstilling i stor mâlestok. Encainid, der kemisk 15 betegnes 4-methoxy-2/-[2-(l-methyl-2-piperidyl)ethyl3benzanilid, til-horer en sérié antiarrhythmiske 2-phenethylpiperidiner, som bærer amidsubstituenter i phenylringens ortho-stilling. Encainid,hydrochlo-rid omtales i litteraturen ogsâ som MJ 9067-1 (USAN og USP Dictionary of Drug Names, 1980, p. 122, United States Pharmacopeal Convention, Inc., 20 12601 Twinbrook Parkway, Rockville, Md. 20852, Library of Congress Catalog Card No. 72-88571). Encainid er for tiden under klinisk afprpv-ning som et effektivt antiarrhythmisk middel.
Tidligere syntese af encainid og nært beslagtede forbindelser er beskrevet i fplgende referencer.
25 Dykstra, S.J. et al., J. Med. Chem., 16, 1015-1020 (1973).
S.J. Dykstra og J.L. Minielli, USA patentskrift nr. 3.931.195, udstedt 28. december 1978, USA patentskrift nr. 4,064.254, udstedt 20. december 1977.
Byrne, J.E. et al., 0. Pharmacology and Experimental Therapeutics, 30 200, 147-154 (1977).
Den i de ovennævnte referencer beskrevne fremgangsmâde, som har været anvendt til fremstilling af encainid, er vist i skema 1.
35
DK 156648 B
2
Skema 1 5 OC"0 ^ Ck ^^NO- " -^Shj AC2^ ' .. V-»02 (l) ' (Z) (3)
Trin 2 VPd 10
G jQ
l\JJ Cl! CILSO. , Trin 3b Trin 3a J™ - (CH3>2S04 CH^O-^o)-COC1 15 οΛΑΐ ™2 (4> (5) 20 Trin 4 . Hj/Pt -> (L) 25
Det f0rste trin ved den i skema 1 viste fremgangsmâde involverer, at man starter med ortho-nitrobenzaldehyd (1), der er et relativt kost-bart materiale, og et formai med den foreliggende opfindelse var at anvise en fremgangsmâde, hvor man gâr ud fra et lettere tilgængeligt, 30 mindre kostbart udgangsmateriale. Oparbejdning af reaktionsblandingen fra trin 3 i skema 1 giver en rpd olie, som opldses i acetonitril og behandles med dimethylsulfat (3b), et toxisk alkyleringsmiddel, under dannelse af 2-[2-[2-(4-methoxybenzamido)phenyl]ethylJ-1-methyl-pyridinium-methylsulfat (5). Trin 4 er hydrogeneringen af en al koholi sk 35 opldsning af (5) under anvendelse af en platin-katalysator.
Den i skema 1 belyste hidtil kendte fremgangsmâde er derfor en flertrinsfremgangsmâde, som anvender kostbare og farlige râmaterialer. I modsætning hertil anvender fremgangsmâden if0lge den foreliggende opfin- 3
DK 156648 B
de!se et mindre kostbart, kommercielt tilgængeligt udgangsmateriale, den kræver mindre arbejdskraft, undgâr toxiske alkyleringsmidler og tilveje-bringer ait i ait encainid af hdj kvalitet for lavere omkostninger.
De fdlgende referencer vedrprer enkelttrin af den foreliggende, her 5 beskrevne fremgangsmâde.
1. H. Stephan og G. Wadge, J. Chem. Soc, 4420 (1956). Denne reference beskriver methyl-N-p-anisoyl-anthranilat, et mellemprodukt, som fremstilles ved den omhandlede fremgangsmâde.
2a. J.F. Wolfe, D.E. Portlock og D.J. Feuerbach, Journal of Organic 10 Chemistry, 39, 2006-2010 (1974).
2b. R. Levine og S. Reynolds, J. Organic Chemistry, 25, 530-537 (1960).
2c. N. Goldberg og R. Levine, Journal American Chemical Society, 74, 9217-5219 (1952).
2d. N. Goldberg, L. Barkley og R. Levine, Journal American Chemical 15 Society, 73, 4301-4303 (1951).
Disse referencer beskriver acyleringen af métallerede methyl-heteroaromater med non-enoliserbare estere, under henvisning til omfang, mekanisme og anvendelse af reaktionen. Acyleringen af métalleret 2-picolin ved den her omhandlede fremgangsmâde er én specifik anvendelse 20 af denne reaktionstype.
Den foreliggende opfindelse angâr en forbedret synteseproces, som kan tilpasses til fremstilling i stor mâlestok af det antiarrhythmiske middel encainid, der kemisk betegnes 4-methoxy-2'-[2-(l-methyl-2-pîperidyl)ethyljbenzani1id. Den foreliggende fremgangsmâde, som gâr ud 25 fra methylanthranilat, et billigt handelskemikalie, udmærker sig ved en ny lavtryks-hydrogeneringssekvens, der omdanner en let fremstillet prækursor direkte til encainid. Den omhandlede fremgangsmâde omfatter i det væsentlige tre trin og frembyder fordele vedrdrende pkonomi for udgangsrâmateriale og arbejdsomkostninger samt fordget egnethed til 30 anvendelse ved standard kemisk procesudstyr i st0rre mâlestok.
Sâledes tilvejebringer den foreliggende opfindelse en fremgangsmâde til fremstilling af 4-methoxy-2,-[2-(î-methyl-2-piperidyl)ethyl]-benzanilid (I) 35
DK 156648 B
4 OCH3 10 (I) hvilken fremgangsmâde er ejendommelig ved, at man a) omsætter methyl-N-p-anisoylanthranilat (III) 15 0 ” "0 och3 (III) 25 med 2-picolyl1ithium tll dannelse af 2-(2-pyridylacetyl)-p-anisanilid (II)
30 X^X
510] X HH (II) 5
DK 156648 B
b) danner et syreadditionssalt af (II), c) hydrogenerer dette syreadditionssalt i iseddikesyre i nærværelse af en platinkatalysator, indtil hydrogenoptagelsen nâr 3 ækvivalenter, d) erstatter platinkatalysatoren med palladium-pâ-carbon kataly-5 sator og fortsætter hydrogenering, indtil 2 yderligere ækvivalenter hydrogen er absorberet, og e) tilsætter overskud af 37% formai in og fortsætter hydrogenering, indtil hydrogenabsorption ophdrer.
Det f0lgende reaktionsskema 2 belyser fremstillingen af encainid ud 10 fra let tilgængelige udgangsmaterialer under anvendelse af den fore-liggende fremgangsmâde. Trin 3 belyser den nye bydrogeneringssekvens.
Skema 2 15 n o rnci „ ©S * à oo
ni!2 Y I
ocu3 h2o, ch2ci2 0 (V) (TV) ^\cn (III) 3 2-picolin n-BuLi_^ 25 . Trin 2 30 , Trin 3
1 l) Pt/n2 F
2) Pd/M2 0. γΑ 3) Pd/H2, CH20 XoCH3 (II) 35
DK 156648B
6
Trin 1 i det ovenfor viste skema involverer omsætning af methyl-anthranilat (V) og p-anisoylchlorid (IV) til dannelse af mellemproduktet methyl-N-p-anisoylanthranilat (III). Udgangsmaterialerne for trin 1 er kommercielt tilgængelige. Trin 2 udfpres ved at behandle (III) med 2-5 picolyllithium (fremstillet ud fra 2-picolin, diisopropylamin og n-butyllithium) under dannelse af 2-(2-pyridylacetyl)-p-anisanilid (II).
En omdannelse af mellemproduktet (II) til encainid (I) via trin 3 repræsenterer en ny hydrogeneringssekvens, som tillader den direkte reduktion af (II) til (I) uden isolering af noget mellemprodukt. Denne 10 sekvens bestâr af omrpring af hydrochloridsaltet af (II) med Pt02 under Hg i iseddikesyre ved omkring stuetemperatur, indtil mindst tre ækvi-valenter H2 er blevet absorberet. PlatinkataTysatoren fjernes og erstattes af tilsat tpr Pd/C katalysator, og den resulterende blanding omr0res under H2 med opvarmning, indtil yderligere to ækvivalenter H2 er 15 blevet absorberet. Blandingen afkples dernæst til omkring stuetemperatur, overskud af 37% formai in tilsættes og blandingen omrpres, indtil al Hg-absorption ophprer. Oparbejdning af reaktionsblandingen tillader direkte isolering af encainid,hydrochlorid. Denne hydrogeneringssekvens gpr den foreliggende fremgangsmàde operabel, hvilken frem-20 gangsmâde producerer encainid i godt udbytte under anvendelse af let tilgængelige, billige udgangsmaterialer. Endvidere er denne fremgangs-mâde velegnet til opskalering til kemisk procesudstyr i stor mâlestok.
Det mindre behov for hândtering af mellemprodukter ved den omhandlede fremgangsmàde i forhold til den ældre fremgangsmàde reducerer omkost-25 ningerne til arbejdskraft.
Hele syntesen af encainid som repræsenteret ved den omhandlede fremgangsmàde udfpres fortrinsvis som en sérié af tre trin, idet man gàr fra de simpleste udgangsmaterialer (methylanthranilat, p-anisoylchlorid og 2-picolin) til encainid,hydrochlorid. De trin, som udgpr fremgangs-30 mâden, er fplgende: (1) p-anisoylchlorid sættes til en omrprt, afkplet oplpsning af methylanthranilat og 50% natriumhydroxid i methylchlorid-vand. Den om-rprte reaktionsblanding henstâr til opvarmning til stuetemperatur til dannelse af methyl-N-p-anisoylanthranilat (III) i omtrentlig 35 95% udbytte.
(2) (III) sættes til en omrprt, kold oplpsning af 2-picolyTlithium (for-dannet ud fra n-butyllithium, diisopropylamin og 2-picolin) i et for reaktionen inert oplpsningsmiddel, sâsom tetrahydrofuran.
DK 156648 B
7
Den omrerte reaktionsblanding henstâr til opvarmning ti1 stuetem-peratur til dannelse af 2-(2-pyridylacetyl)-p-anisanilid (II).
(3) (II) hydrogeneres i iseddikesyre i nærværelse af en platinkata-lysator, f.eks. PtOg eller carbon-understpttet Pt, indtil hydrogen-5 optagelsen nàr tre ækvivalenter, Pt katalysatoren erstattes af palladium-pâ-carbon katalysator og hydrogenering fortsættes, indtil yderligere to ækvival enter hydrogen er blevet absorberet, og dernæst tilsættes overskud af 37% formai in til reaktionsblandingen og hydrogenering fortsættes, indtil al hydrogenabsorption ophprer.
10 Katalysatoren fjernes og produktet (I) isoleres direkte i ca. 75% udbytte.
Fremgangsmâden ifplge den foreliggende opfindelse belyses nærmere i de fplgende eksempler.
15 Eksempel 1
Methvl-N-p-anisovlanthranilat (III)
En oplpsning af 529,8 g (3,505 mol) methylanthranilat og 294,4 g 50 vægt% NaOH (3,68 mol) i 3,6 1 Ct^Clg og 1,8 1 HgO omrprtes i et is-bad, mens 627,8 g (3,680 mol) p-anisoylchlorid blev tilsat med en sâdan 20 hastighed, at temperaturen ikke oversteg 10°C (den npdvendige tid var 1,25 timer). Blandingen henstod til opvarmning til 23°C. Eddikesyre (50 ml) tilsattes til justering af pH-værdien til 5. Lagene adskiltes og det organiske lag vaskedes med 10% vandig NaHCOg (1 x 0,8 1) og saltvand (1 x 0,8 1). Oplpsningsmidlet fjernedes i vakuum. Det tilbageblevne hvide, 25 faste stof omkrystalliseredes fra 7,0 1 kogende methanol. Produktet (III) tprredes i vakuum ved 70°C i 24 timer til et udbytte pâ 959,7 g (96,0%) hvidt, krystallinsk fast stof, smp. 122,5-124,5°C.
Eksempel 2 30 2-12-pvridvlacetvll-p-anisanilid (II)
En tpr, nitrogenskyllet kolbe fyldtes med 1,875 ml 1,6 N (3,0 mol) n-butyllithium i hexan. Oplpsningen omrprtes under nitrogen og afkpledes til -45° til -40°C, og 1,5 1 THF (tprret over molekylsi 4 A) tilsattes langsomt. Diisopropylamin (303,6 g, 3,0 mol) tilsattes ved en sâdan 35 hastighed, at temperaturen ikke oversteg -30°C. Dernæst tilsattes 307,3 g (3,3 mol) 2-picolin under omrpring, idet temperaturen holdtes under -30°C. Afkplingen blev afbrudt og blandingen langsomt opvarmet til 10°C, pâ hvilket tidspunkt omdannelsen til anion var komplet og al 2-picolyl-
DK 156648 B
8 lithium var blevet genoplpst. Oplpsningen genafkpledes til -45° ti1 ~40°C (oramgefarvet, fast stof genudfældede), og en oplpsning af 285,3 g (1,0 mol) methyl-N-p-anisoylanthranilat (III) i 1,9 1 t0r THF tilsattes ved en sâdan hastighed, at temperaturen ikke oversteg -30°C. Efter 5 tilsætningen opvarmedes blandingen langsomt til 25°C. Oplesningen ind-stilledes pâ pH-værdi 6 med 500 ml eddikesyre, 5,0 1 HgO tilsattes under omwing. Dernæst destilleredes de organiske opl0sningsmidler i vakuum og det tilbageblevne, gule halvfaste produkt ekstraheredes med CHgClg (1 x 2,5 1). Ekstrakten vaskedes med H2O (1 x 1,0 1) og strippedes til 10 tsrhed i vakuum. Remanensen opl0stes i 6,7 1 kogende isopropanol. Qplps-ningen afkpledes under omrdring til 5 ±5°C, og det resulterende gule faste stof opsamledes pâ et fil ter, skylledes med isopropanol og tprredes i vakuum ved 80°C i seks timer. Filtratet koncentreredes og afkpledes til dannelse af et andet udbytte af produktet. Begge udbytter 15 af intenst gult materiale udviste enkelt-pletter ved TLC (7,5 cm si!ica-gel med indikator, 9 CHgClg : 1 methanol, UV). Det totale udbytte var 306,7 g (88,5%) materiale, smp. 145-148,5°C.
Eksemoel 3 20 Fremstillina af fil) i stor mâlestok
En t0r, med nitrogen skyllet, ca. 380 1 rustfri stâlreaktor fyldes med tetrahydrofuran (47 kg). THF'en afkples til 5°C eller mindre. Langsomt tilsættes 15% n-butyllithium i hexan (37 kg x 0,152 * 5,62 kg n-butyllithium; 87,6 mol) til THF'en med en sâdan hastighed, at reak-25 tionstemperaturen holdes under 5°C. Langsomt tilsættes diisopropylamin (8,9 kg; 87,9 mol) til blandingen med en sâdan hastighed, at reak-tionstemperaturen holdes under 5°. Langsomt tilsættes 2-picolin (8,3 kg; 89,1 mol) til reaktionsoplpsningen med en hastighed, som holder reak-tionstemperaturen pâ mindre end 5°C. I en separat reaktor opldses N-p-30 anisoylanthranilat (7,7 kg; 27 mol) i varm (ca. 30°C) THF (47 kg). Denne oplisning sættes langsomt til 2-picolyllithium-blandingen med en hastighed, som holder reaktionstemperaturen under 10°C. Efter endt ti1 -sætning opvarmes blandingen til ca. 20°C og omrpres i 15 minutter. En ca. 1900 Hier glasforet reaktor fyldes med HgO (135 kg) og eddikesyre 35 (13,5 kg; 224,6 mol). Blandingen afkdles til ca. 0°C og THF-opl0sningen sættes til denne afkdlede blanding. HgO-laget (nederst) fraskilles og vaskes med methylenchlorid (2 x 58 kg). De organiske lag forenes og koncentreres i vakuum. Isopropanol (143 kg) tilsættes og blandingen
DK 156648 B
9 opvarmes til tilbagesvaling. Blandingen koncentreres i vakuum til halvt volumen og afkdles til ca. 0°C. Det faste stof opsamles og vaskes med isopropanol (2x6 kg). Det faste stof tprres ved ca. 40°C under vakuum til et udbytte pâ 8,25 kg (89%) af produkt (II).
5
Eksempel 4 2-(2-pvridvlacetv1)-p-anisanilid.hvdrochlorid (II hvdrochlorid) 2-(2-pyridylacetyl)-p-anisanilid (II) (25,0 g, 0,0722 mol) oplpstes under mild opvarmning i 500 ml THF. Den klargule opldsning afkdledes pâ 10 et isbad og 6,5 ml (0,078 mol) 12 N HCl tilsattes. Den gule farve for-svandt og et hvidt bundfald dannedes umiddelbart. Det faste stof opsam-ledes pâ et fil ter, skylledes med THF og luftt0rredes til dannelse af 27,4 g hvidt, fast stof (99,3%), smp. 190,5-191,5° (dek.) 15 Eksempel 5 4-methoxv-2/-r2-(l-methvl-2-piperidvl)ethvllbenzanilid Π). encainid En blanding af 53,5 g (0,1397 mol) 2-(2-pyridylacetyl)-p-anis-anilid,hydrochlorid, 1,0 g pTatinkatalysator (2,5-5% Pt/C eller PtO2) og 1,0 1 iseddikesyre omrprtes kraftigt under et let positivt H2-tryk .20 ved 23-25°C i 20 timer, pâ hvilket tidspunkt 0,43 mol (3,08 ækvivalen-ter) H, var blevet absorberet. Katalysatoren fjernedes ved filtrering gennem et Celite -leje. Filtratet ledtes tilbage til kolben og 10,0 g 10% Pd/C tilsattes under nitrogen. Blandingen omrprtes kraftigt under Hg, idet den opvarmedes til 60 ± 3°C. Efter yderligere 6,5 timer 25 udgjorde den totale H^-optagelse 0,71 mol (5,08 ækvivalenter, 101,6% teori). Blandingen afkpledes til 25°C og 22,7 g formai in (37 vægt% formaldehyd, 8,4 g, 0,28 mol) indsprpjtedes i reaktionsblandingen.
Blandingen omrprtes kraftigt under H2 ved 23-25°C i 20 timer; i ldbet af dette tidsrum blev 0,1452 mol (1,04 ækvivalenter) H2 absorberet.
30 Katalysatoren fjernedes ved filtrering og filtratet koncentreredes i vakuum til en tyk olie. Olien blandedes to gange med 200 ml isopropanol og strippedes i vakuum ved 90°C til en tyk olie. Olien oplpstes i 200 ml kogende isopropanol. Oplpsningen omrprtes, podedes med (I) og afkpledes til 10°C i 1 time. Det faste stof opsamledes pâ et filter, skylledes med 35 kold isopropanol (2 x 2,0 ml) til dannelse af 36,6 g (67,4%) produkt, smp. 181,5-184,5°C. Yderligere produkt opnâedes fra isopropanol-filtratet til et totalt udbytte pâ 76,1% encainid.
Claims (2)
1. Fremgangsmâde til fremstilling af 4-methoxy-2,-[2-(l-methyl--2-pi peri dyl)ethyl]benzani1i d (I) ίο Oc» (I)
15 KENDETEGNET ved, AT man a) omsætter methyl-N-p-anisoylanthranilat (III) o ifTl 0CH3 20 N/ ^NH OCH3 25 (III) med 2-picolyllithium til dannelse af 2-(2-pyri dylacety1)-p-an i s an i1i d (Π) 30 Ijü] 35 °%1 \^oc>i3 (II) DK 156648 B u b) danner et syreadditionssalt af (II), c) hydrogenerer dette syreadditionssalt i iseddikesyre i nærværelse af en platinkatalysator, indtil hydrogenoptagelse nâr 3 ækvivalenter, d) erstatter platinkatalysatoren med palladium-pà-carbon katalysa-5 tor og fortsætter hydrogeneringen, indtil 2 yderligere ækvival enter hydrogen er blevet absorberet, og e) tilsætter overskud af 37% formai in og fortsætter hydrogenering, indtil hydrogenabsorption ophorer.
2. Fremgangsmâde ifolge krav 1, KENDETEGNET ved, AT hydrochlorid-10 saltet af 2-(2-pyridylacetyl)-p-anisanilid omrires med en platinkatalysator under hydrogen ved et let positivt tryk i iseddikesyre ved omtrentlig stuetemperatur, indtil tre ækvivalenter hydrogen er blevet absorberet, platinkatalysatoren fjernes ved filtrering og tdr palladium-pâ-carbon katalysator tilsættes filtratet og omwing af denne reak-15 tionsblanding fortsættes under hydrogen ved 55° til 95°, indtil yderligere to ækvivalenter er blevet absorberet, blandingen afkples til 25° eller mindre og 37% formai in indspr0jtes i overskud i reaktions-blandingen efterfulgt af omrdring under hydrogen ved 20° til 40°C, indtil al hydrogenabsorption ophorer. 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33029881 | 1981-12-14 | ||
| US06/330,298 US4394507A (en) | 1981-12-14 | 1981-12-14 | Process for production of encainide |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK551582A DK551582A (da) | 1983-06-15 |
| DK156648B true DK156648B (da) | 1989-09-18 |
| DK156648C DK156648C (da) | 1990-03-05 |
Family
ID=23289147
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK551582A DK156648C (da) | 1981-12-14 | 1982-12-10 | Fremgangsmaade til fremstilling af 4-methoxy-2'-(2-(1-methyl-2-piperidyl)ethyl)benzanilid (encainid) |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4394507A (da) |
| JP (1) | JPS6058231B2 (da) |
| KR (1) | KR890000419B1 (da) |
| AT (1) | AT378182B (da) |
| CA (1) | CA1213282A (da) |
| CH (1) | CH655101A5 (da) |
| DK (1) | DK156648C (da) |
| ES (2) | ES517996A0 (da) |
| FI (1) | FI76561C (da) |
| GR (1) | GR77107B (da) |
| HU (1) | HU186190B (da) |
| IT (1) | IT1149399B (da) |
| NL (1) | NL8204775A (da) |
| PT (1) | PT75980B (da) |
| SE (1) | SE454442B (da) |
| YU (1) | YU44035B (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4675409A (en) * | 1986-02-25 | 1987-06-23 | Bristol-Myers Company | Process for the preparation of encainide |
| US4800226A (en) * | 1986-02-25 | 1989-01-24 | Bristol-Myers Company | Process intermediate for the preparation of encainide |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2317303A (en) * | 1940-12-07 | 1943-04-20 | Merck & Co Inc | Heterocyclic nitrogen containing compounds, and processes for making the same |
| CA961038A (en) * | 1971-03-03 | 1975-01-14 | Bristol-Myers Canada Limited | Substituted piperidines |
| US4000143A (en) * | 1971-03-03 | 1976-12-28 | Mead Johnson & Company | Substituted piperidines |
| US4064254A (en) * | 1971-03-03 | 1977-12-20 | Mead Johnson & Company | Substituted piperidines therapeutic process and compositions |
| US3931195A (en) * | 1971-03-03 | 1976-01-06 | Mead Johnson & Company | Substituted piperidines |
| SE7607114L (sv) * | 1976-06-22 | 1977-12-23 | Bofors Ab | Sett att framstella hydrokloriden av n-metylpiperidin-2-karbonsyra-2,6-xyllidid |
-
1981
- 1981-12-14 US US06/330,298 patent/US4394507A/en not_active Expired - Fee Related
-
1982
- 1982-11-18 GR GR69848A patent/GR77107B/el unknown
- 1982-11-22 CA CA000416079A patent/CA1213282A/en not_active Expired
- 1982-11-25 KR KR8205318A patent/KR890000419B1/ko not_active Expired
- 1982-12-02 IT IT49608/82A patent/IT1149399B/it active
- 1982-12-07 YU YU2710/82A patent/YU44035B/xx unknown
- 1982-12-07 ES ES517996A patent/ES517996A0/es active Granted
- 1982-12-09 FI FI824234A patent/FI76561C/fi not_active IP Right Cessation
- 1982-12-09 JP JP57214747A patent/JPS6058231B2/ja not_active Expired
- 1982-12-09 NL NL8204775A patent/NL8204775A/nl unknown
- 1982-12-10 DK DK551582A patent/DK156648C/da not_active IP Right Cessation
- 1982-12-13 SE SE8207112A patent/SE454442B/sv not_active IP Right Cessation
- 1982-12-13 CH CH7245/82A patent/CH655101A5/de not_active IP Right Cessation
- 1982-12-13 HU HU824018A patent/HU186190B/hu not_active IP Right Cessation
- 1982-12-13 PT PT75980A patent/PT75980B/pt not_active IP Right Cessation
- 1982-12-14 AT AT0454082A patent/AT378182B/de not_active IP Right Cessation
-
1984
- 1984-03-01 ES ES530218A patent/ES530218A0/es active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| SE8207112D0 (sv) | 1982-12-13 |
| CH655101A5 (de) | 1986-03-27 |
| HU186190B (en) | 1985-06-28 |
| US4394507A (en) | 1983-07-19 |
| JPS6058231B2 (ja) | 1985-12-19 |
| KR840002355A (ko) | 1984-06-25 |
| YU271082A (en) | 1985-03-20 |
| GR77107B (da) | 1984-09-06 |
| FI76561C (fi) | 1988-11-10 |
| YU44035B (en) | 1990-02-28 |
| DK156648C (da) | 1990-03-05 |
| SE8207112L (sv) | 1983-06-15 |
| JPS58105963A (ja) | 1983-06-24 |
| ES8405767A1 (es) | 1984-06-16 |
| KR890000419B1 (ko) | 1989-03-17 |
| ATA454082A (de) | 1984-11-15 |
| AT378182B (de) | 1985-06-25 |
| ES8506274A1 (es) | 1985-07-01 |
| NL8204775A (nl) | 1983-07-01 |
| CA1213282A (en) | 1986-10-28 |
| SE454442B (sv) | 1988-05-02 |
| DK551582A (da) | 1983-06-15 |
| IT8249608A0 (it) | 1982-12-02 |
| IT1149399B (it) | 1986-12-03 |
| FI824234L (fi) | 1983-06-15 |
| FI76561B (fi) | 1988-07-29 |
| PT75980A (en) | 1983-01-01 |
| FI824234A0 (fi) | 1982-12-09 |
| PT75980B (en) | 1985-12-20 |
| ES517996A0 (es) | 1984-06-16 |
| ES530218A0 (es) | 1985-07-01 |
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