DK142280B - Fremgangsmaade til fremstilling af 4-aminopyridiner - Google Patents
Fremgangsmaade til fremstilling af 4-aminopyridiner Download PDFInfo
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- DK142280B DK142280B DK142276A DK142276A DK142280B DK 142280 B DK142280 B DK 142280B DK 142276 A DK142276 A DK 142276A DK 142276 A DK142276 A DK 142276A DK 142280 B DK142280 B DK 142280B
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- DK
- Denmark
- Prior art keywords
- aminopyridines
- preparation
- mole
- hours
- heated
- Prior art date
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- 238000000034 method Methods 0.000 title description 7
- 150000003928 4-aminopyridines Chemical class 0.000 title description 6
- 238000002360 preparation method Methods 0.000 title description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- QZOFFMRDIRXGKJ-UHFFFAOYSA-M hydron;4-pyridin-1-ium-1-ylpyridine;dichloride Chemical compound Cl.[Cl-].C1=CC=CC=[N+]1C1=CC=NC=C1 QZOFFMRDIRXGKJ-UHFFFAOYSA-M 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- FEWLNYSYJNLUOO-UHFFFAOYSA-N 1-Piperidinecarboxaldehyde Chemical compound O=CN1CCCCC1 FEWLNYSYJNLUOO-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000047 product Substances 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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000010933 acylation Effects 0.000 description 3
- 238000005917 acylation reaction Methods 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- -1 pyrrolidine Chemical class 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- AVQQQNCBBIEMEU-UHFFFAOYSA-N 1,1,3,3-tetramethylurea Chemical compound CN(C)C(=O)N(C)C AVQQQNCBBIEMEU-UHFFFAOYSA-N 0.000 description 2
- NUKYPUAOHBNCPY-UHFFFAOYSA-N 4-aminopyridine Chemical compound NC1=CC=NC=C1 NUKYPUAOHBNCPY-UHFFFAOYSA-N 0.000 description 2
- GEIZYPUHEGXPEQ-UHFFFAOYSA-M 4-pyridin-1-ium-1-ylpyridine;chloride Chemical compound [Cl-].C1=CC=CC=[N+]1C1=CC=NC=C1 GEIZYPUHEGXPEQ-UHFFFAOYSA-M 0.000 description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 description 2
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 2
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 2
- 125000003341 7 membered heterocyclic group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229960004979 fampridine Drugs 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- LCEDQNDDFOCWGG-UHFFFAOYSA-N morpholine-4-carbaldehyde Chemical compound O=CN1CCOCC1 LCEDQNDDFOCWGG-UHFFFAOYSA-N 0.000 description 2
- LSCYTCMNCWMCQE-UHFFFAOYSA-N n-methylpyridin-4-amine Chemical compound CNC1=CC=NC=C1 LSCYTCMNCWMCQE-UHFFFAOYSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- AGRIQBHIKABLPJ-UHFFFAOYSA-N 1-Pyrrolidinecarboxaldehyde Chemical compound O=CN1CCCC1 AGRIQBHIKABLPJ-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- PVMNPAUTCMBOMO-UHFFFAOYSA-N 4-chloropyridine Chemical compound ClC1=CC=NC=C1 PVMNPAUTCMBOMO-UHFFFAOYSA-N 0.000 description 1
- GCNTZFIIOFTKIY-UHFFFAOYSA-N 4-hydroxypyridine Chemical compound OC1=CC=NC=C1 GCNTZFIIOFTKIY-UHFFFAOYSA-N 0.000 description 1
- OATKXQIGHQXTDO-UHFFFAOYSA-N 4-phenoxypyridine Chemical compound C=1C=NC=CC=1OC1=CC=CC=C1 OATKXQIGHQXTDO-UHFFFAOYSA-N 0.000 description 1
- MTPBUCCXRGSDCR-UHFFFAOYSA-N 4-piperidin-1-ylpyridine Chemical compound C1CCCCN1C1=CC=NC=C1 MTPBUCCXRGSDCR-UHFFFAOYSA-N 0.000 description 1
- QJWQYVJVCXMTJP-UHFFFAOYSA-N 4-pyridin-4-ylmorpholine Chemical compound C1COCCN1C1=CC=NC=C1 QJWQYVJVCXMTJP-UHFFFAOYSA-N 0.000 description 1
- 101100188555 Arabidopsis thaliana OCT6 gene Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 239000003929 acidic solution Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003245 coal Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000011491 glass wool Substances 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- ZGEGCLOFRBLKSE-UHFFFAOYSA-N methylene hexane Natural products CCCCCC=C ZGEGCLOFRBLKSE-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- SVEUVITYHIHZQE-UHFFFAOYSA-N n-methylpyridin-2-amine Chemical compound CNC1=CC=CC=N1 SVEUVITYHIHZQE-UHFFFAOYSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
-
- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Description
féat' I Ism \r&> (11) FREMLÆGGELSESSKRIFT 1A-2280 DANMARK (».) Int el.. C 07 D 213/72 • (21) Ansøgning nr. 1422/76 (22) Indleveret den JO. mar. 1976 (24) Løbedag JO. mar. 1976 (44) Ansøgningen fremlagt og fremlseggelsesskriftet offentliggjort den 6. okt · 1980
DIREKTORATET FOR
PATENT-OG VAREMÆRKEVÆSENET (30) Prioritet begæret fra den
18. apr. 1975a 2517774, DE
(71) SOBERING AKTIENGESET iLSCHAFT, Berlin und Bergkamen, Mu ellers træ s e 170— T78, 1 Berlin 65, DE.
(72) Opfinder i Helmut Vorbrueggen, Wilkestr. 7a 1 Berlin 27a DE.
(74) Fuldmægtig under sagens behandling:
Firmaet Chas. Hude.________ (54) Fremgangsmåde til fremstilling af 4-aminopyridiner.
Den foreliggende opfindelse angår en hidtil ukendt fremgangsmåde til fremstilling af 4-aminopyridiner med den i kravets indledning angivne almene formel (I).
De fremstillede produkter tjener især som acyleringskatalysatorer eller er også egnede som mellemprodukter til fremstilling af virksomme lægemidler.
Til selektiv og hurtig acylering af aminer /Z.K. Litvinenko m.fl., C.A. 68, 68325u (1968J7 og alkoholer £fS. Steglich og G. HOfle, Angew.
Chemie 81, 1001 (1969), Tetrahedron Letters 4727 (1970) og Synthesis 1972, 619/ er det almindeligt at anvende 4-dialkylaminopyridiner og 2 142280 af disse især 4-dimetylaminopyridin og 4-pyrrolidinopyridin som acy-leringskatalysatorer (DOS 1.958.954, DOS 2.137.856). De hidtil kendte fremstillingsmåder for substituerede 4-aminopyridiner er imidlertid vanskelige. Desuden kan de nødvendige udgangsmaterialer kun fremstilles via flere komplicerede trin. Således bliver f.eks. enten 4-klorpyridin amineret med dimetylamin ved 150°C under tryk /1. Pen-timalli, G-azz. Chim. I tal. 94, 902 (1964.)/ eller silyleret 4-pyridon under sur katalyse omsat med aminer, som f.eks. pyrrolidin, /H. Vor-brtlggen, Ingew. Chemie 84, 348 (1972J.7 eller 4-pyridyl-fenylæter /D. Jerchel m.fl., Chem. Ber. 91, 1266 (1958.)/ omdannes med sekundære aminer til de tilsvarende 4-<iialkylaminopyridiner. Fra beskrivelsen til tysk patent nr. 536.891 er det kendt at fremstille 4-aminopyridiner ved omsætning af 4-pyridylpyridiniumklorid eller et salt deraf med am= moniak eller organiske aminer/ men udhyttet er meget ringe.
Det har nu vist sig, at de nævnte 4-aminopyridiner kan fremstilles på teknisk brugbar måde og på simpel måde direkte af det let tilgængelige 4-pyfiåyl-pyridiniumklorid eller et salt deraf, fortrinsvis hydrokloridet, ved omsætning med et ligeledes let tilgængeligt egnet syreamid.
Opfindelsen angår således en fremgangsmåde til fremstilling af 4-amino= pyri diner med den almene formel I
R1 R2 rT^ (I) 2 hvor R og R er ens eller forskellige og betyder hydrogen eller en alkylgruppe med 1-6 kulstofatomer eller sammen med N-atomet danner en 2
5-, 6- eller 7-leddet heterocyklisk mættet ring, der yderligere kan indeholde et eller flere heteroatomer, og fremgangsmåden er ejendommelig ved, at man ved en temperatur på 120-220°C omsætter 4-pyridylpyridiniumklorid eller et salt deraf med et syreamid med den almene formel II
3 142280
^ N - Z
(11¾
R
12 3 hvor R og R har den ovennævnte betydning, og Z er gruppen —CO—R , R1
3 S
hvor R er hydrogen, alkyl med 1-6 kulstofatomer eller N , eller (2 NR2 z er gruppen ~PO J2' hvor °9 r2 ^ar den ovennævnte betyd ning .
1 2 3
Med R , R og R som alkylgrupper med 1-6 kulstofatomer, menes lige-kædede og forgrenede, mættede kulbrinterester, som f.eks. metyl, ætyl, propyl, isopropyl, butyl, isobutyl, sek.-butyl, pentyl, hexyl, tert.-butyl og især de med 1-4 kulstofatomer. Når R og R sammen med nitrogenatomet danner en 5-, 6- eller 7-leddet heterocyklisk ring, der yderligere kan indeholde et eller flere heteroatamer, fortrinsvis et yderligere heteroatom, f.eks. N, O eller S, forstås herved hydre- Λ rede heterocykler, såsom pyrrolidin, piperidin, N -alkylpiperazin, morfolin, tiomorfolin og azepin. Foretrukne er de med 5 eller 6 ringled.
Som syreamider med den almene formel II forstås især amider af middelstærke og svage syrer, fortrinsvis myresyre, eddikesyre, kulsyre og fosforsyre.
Som syreamider skal f.eks. nævnes: dimetylformamid, dimetylacetamid, tetrametylurinstof, hexametylfosforsyretriamid, F-formylpyrrolidin, N-formylpiperidin, F-formylmorfolin, F-metylformamid, F-metylacetamid, formamid, urinstof og acetamid.
Ved udførelse af fremgangsmåden ifølge opfindelsen tjener det anvendte syreamid med den almene formel II i reglen også samtidig som opløsningsmiddel, hvilket ikke udelukker, at man til reaktionsblandingen eventuelt yderligere sætter et indifferent organisk opløsningsmiddel som fortyndingsmiddel eller opløsningsformidler. Hvis syrea-midet foreligger i fast form, sker omsætningen i smeltet tilstand el- 4 142230 ler eventuelt i nærværelse af et indifferent organisk opløsningsmiddel. Reaktionsdeltagerne kan omsættes i molære mængder, men hensigtsmæssigt anvendes syreamidet i overskud, fortrinsvis 1-5 ækvivalenter. Omsætningen sker ved forhøjet temperatur, f.eks. ved kogepunktet af det anvendte syreamid eller opløsningsformidleren.
For at opnå optimale udbytter af det ønskede produkt er det hensigtsmæssigt at fjerne det under omsætningen opståendepyridin kontinuerligt fra reaktionsblandingen, f.eks. over en kort destillationskolonne. Reaktionen er afsluttet, når ca. 1 mol dannet pyridin pr. mol4-pyri= dyl- pyridiniumklorid er af destilleret. Isoleringen af det fremstillede produkt sker på sædvanlig måde, f.eks. ved at man til reaktionsblandingen sætter vandig alkali i overskud, fortrinsvis 2-3 mol, og fraskiller produktet ved vanddampdestillation eller udtømmende ekstraktion, f.eks. med metylenklorid.
Eksempel 1 229 g (l mol) rå 4-pyridyl-pyridiniumkloridhydroklorid (Org. Synthesis Coll, hind ¥, 977) blev opløst i 146,2 g (2 mol) dimetylformamid ved ca. 140-150°C og opvarmet under omrøring i 2 timer ved en hadtemperatur på 180°C, hvorved der af destillerede 90 ml rå pyridin (kogepunkt 111-122°C). Een mørke remanens lod man henstå med 100 g EaOH i 1 liter HgO, filtrerede fra sort uopløselig remanens og ekstraherede remanens og opløsning udtømmende med metylenklorid. Efter tørring af metylenkloridekstrakterne (hagSO^) og behandling med lidt kul fremkom 68,3 g (56$) rå 4-dimetylaminopyridin, som efter omkrystallisation af diisopropylæter smeltede ved 112-113°C.
Eksempel 2
Som eksempel 1, kun at der i stedet for 146,2 (2 mol) dimetylformamid blev anvendt 174 g (2 mol) dimetylacetamid. Efter opvarmning i 2 timer til 130°C og oparbejdning fremkom 74,2 g (61%) 4-dimetylaminopyridin.
Eksempel 3
Ved opvarmning i 2 timer til 180°C og iøvrigt som i eksempel 1, kun at der i stedet for dimetylformamid blev anvendt 2-3 mol tetrametyl-urinstof. Udbyttet var 56% 4-dimetylaminopyridin med smeltepunkt 5 142280 112-113°C.
Eksempel 4 229 g (1 mol) 4-pyridyl-pyridiniumkloridhydroklorid i 179 g (l mol) hexametylfosforsyretriamid "blev under omrøring og afdestillation af pyridlnen (40 ml) opvarmet i 1 time til 220°C. Efter afkøling optog man remanensen i 500 ml H20 og opvarmede i 1 1/2 time på dampbad.
Den svagt sure opløsning (pH ca. 5) filtrerede man over et blødt foldefilter og vaskede den uopløselige brune del to gange med hver 100 ml 2N HC1. Det forenede filtrat blev gjort stærkt alkalisk med ca. 200 ml 40$ Ε0Η og ekstraheret udtømmende med metylenklorid. Efter tørring (Na2S0^) og afdampning udkogte man den tilbageblevne seje olie (107j59 g) med 1,5 liter diisopropylæter og behandlede med lidt kul. Af filtratet krystalliserede ved 4°C 65,79 g (53,8$) ren 4-di= metylaminopyridin, smeltepunkt 112-113°C.
Eksempel 5 22.9 g (0,1 mol) rå 4-pyridyl-pyridiniumkloridhydroklorid i 30 g (0,3 mol) N-formylpyrrolidin blev opvarmet i 3 1/2 time under omrøring til 180°C, hvorved pyridin afdestillerede. Den mørke remanens blev henstillet natten over med 250 ml 2H HaOH og ekstraheret udtømmende med metylenklorid. Ekstrakterne gav efter tørring (Ba^SO^), behandling med kul og afdampning 11,5 g brun olie, som blev udkogt flere gange med metylenklorid/hexan. Ekstrakterne omkrystalliserede man af hexan, hvorved der fremkom 8,95 g (60,5$) 4-pyrrolidino-pyri= din, smeltepunkt 55-57°C.
Eksempel 6 22.9 g (0,1 mol) rå 4-pyridyl-pyridiniumkloridhydroklorid blev som beskrevet i eksempel 3 opvarmet i 2 timer til 180°C i 33,9 g (0,3 mol) N-formylpiperidin og oparbejdet, hvorved der efter omkrystallisation af ligroin fremkom 4,35 g (58%) 4-piperidinopyridin, smeltepunkt 81°C.
Eksempel 7
Helt analogt med eksempel 5 og 6 ved opvarmning i 2 timer til 180°C gav reaktion af 4-pyridyl-pyridiniumkloridhydroklorid med N-formylmorfolin 142280 6 i et udbytte på 59% 4-morfolinopyridin med smeltepunkt 93—95°C (af lxgroin).
Eksempel 8 344 g (1,5 mol) rå 4-pyridyl-pyridiniumkloridhydroklorid i 241 g (4,2 mol) N-metylformamid blev under omrøring opvarmet i 2 1/2 time til 190°C, hvorved 120 ml pyridin afdestillerede. Efter afkøling blev den sorte remanens henstillet i 100 ml 3N NaOH i 16 timer og ekstraheret udtømmende med metylenklorid. Efter tørring (Na2S04), behandling med lidt kul og afdampning fik man 85 g (52,5%) rå gullig krystallinsk 4-metylaminopyridin, som efter om-krystallisation af toluol smeltede ved 121-124°C.
Eksempel 9
Som eksempel 8, kun at der i stedet for H-metylformamid blev anvendt U-metylaeetamid. Udbytte: 55$ 4-metylaminopyridin, smeltepunkt 121-124°C.
Eksempel 10 115 g (0,5 mol) 4-pyridyl-pyridiniumkIoridhydroklorid blev opvarmet under omrøring til 150°C i 100 ml (2,5 mol) formamid, hvorved alt går i opløsning, og derefter forsigtigt og langsomt opvarmet til 180°0 (opløsningen skummer meget) under afdestillation af pyridin. Efter 1 time ved 180°C blev der afkølet og opvarmet med en opløsning af 120 g UaOH i 500 ml HgO i 5 timer på dampbad, og blandingen blev filtreret over glasuld. Een uopløste remanens blev vasket med metylen= klorid, og det sorte alkaliske filtrat blev ekstraheret kontinuerligt udtømmende med metylenklorid, hvorved der fremkom 24,9 g (55$) 4-aminopyridin, smeltepunkt 156-158°C.
Eksempel 11
Som eksempel 10, kun at der blev anvendt acetamid i stedet for form= amid. Udbyttet af 4-aminopyridin var 58$.
Eksempel 12
Som beskrevet i eksempel 10 blev 4-pyridyl-pyridiniumkloridhydroklo-
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19752517774 DE2517774C3 (de) | 1975-04-18 | 1975-04-18 | Verfahren zur Herstellung von 4-Aminopyridinen |
| DE2517774 | 1975-04-18 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK142276A DK142276A (da) | 1976-10-19 |
| DK142280B true DK142280B (da) | 1980-10-06 |
| DK142280C DK142280C (da) | 1981-06-29 |
Family
ID=5944672
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK142276A DK142280C (da) | 1975-04-18 | 1976-03-30 | Fremgangsmaade til fremstilling af 4-aminopyridiner |
Country Status (13)
| Country | Link |
|---|---|
| JP (1) | JPS604817B2 (da) |
| BE (1) | BE840874A (da) |
| CA (1) | CA1054604A (da) |
| CH (1) | CH597189A5 (da) |
| DE (1) | DE2517774C3 (da) |
| DK (1) | DK142280C (da) |
| FR (1) | FR2307802A1 (da) |
| GB (1) | GB1548763A (da) |
| IE (1) | IE43092B1 (da) |
| IT (1) | IT1063241B (da) |
| LU (1) | LU74766A1 (da) |
| MX (1) | MX3299E (da) |
| NL (1) | NL7604013A (da) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4390710A (en) | 1981-10-19 | 1983-06-28 | Ppg Industries, Inc. | Catalyst system for manufacturing p-chlorophenyl-N-methyl carbamate |
| EP1422222B1 (en) * | 1997-08-01 | 2008-12-03 | Vertellus Specialties Inc. | Process for preparing 4-[(di)alkylamino]pyridines |
| WO2024105319A1 (fr) | 2022-11-15 | 2024-05-23 | Stellantis Auto Sas | Structure de véhicule automobile avec renfort de support de train arrière |
-
1975
- 1975-04-18 DE DE19752517774 patent/DE2517774C3/de not_active Expired
-
1976
- 1976-03-30 DK DK142276A patent/DK142280C/da not_active IP Right Cessation
- 1976-04-12 MX MX16676U patent/MX3299E/es unknown
- 1976-04-12 GB GB1481376A patent/GB1548763A/en not_active Expired
- 1976-04-14 LU LU74766A patent/LU74766A1/xx unknown
- 1976-04-14 CH CH478976A patent/CH597189A5/xx not_active IP Right Cessation
- 1976-04-15 NL NL7604013A patent/NL7604013A/xx not_active Application Discontinuation
- 1976-04-15 IE IE80776A patent/IE43092B1/en unknown
- 1976-04-16 FR FR7611335A patent/FR2307802A1/fr active Granted
- 1976-04-16 BE BE166257A patent/BE840874A/xx not_active IP Right Cessation
- 1976-04-16 IT IT2240676A patent/IT1063241B/it active
- 1976-04-19 JP JP4440976A patent/JPS604817B2/ja not_active Expired
- 1976-10-18 CA CA263609A patent/CA1054604A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CH597189A5 (da) | 1978-03-31 |
| LU74766A1 (da) | 1976-11-11 |
| FR2307802A1 (fr) | 1976-11-12 |
| FR2307802B1 (da) | 1979-05-11 |
| JPS604817B2 (ja) | 1985-02-06 |
| MX3299E (es) | 1980-08-29 |
| IT1063241B (it) | 1985-02-11 |
| GB1548763A (en) | 1979-07-18 |
| DE2517774B2 (de) | 1980-02-28 |
| DE2517774A1 (de) | 1976-10-28 |
| CA1054604A (en) | 1979-05-15 |
| BE840874A (fr) | 1976-10-18 |
| NL7604013A (nl) | 1976-10-20 |
| DK142280C (da) | 1981-06-29 |
| IE43092B1 (en) | 1980-12-17 |
| DK142276A (da) | 1976-10-19 |
| JPS51128973A (en) | 1976-11-10 |
| DE2517774C3 (de) | 1980-10-30 |
| IE43092L (en) | 1976-10-18 |
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