DK141333B - Fremgangsmåde til fremstilling af tetrahydro-thieno(3,2-c)- eller-(2,3-c)pyridinderivater. - Google Patents
Fremgangsmåde til fremstilling af tetrahydro-thieno(3,2-c)- eller-(2,3-c)pyridinderivater. Download PDFInfo
- Publication number
- DK141333B DK141333B DK297876AA DK297876A DK141333B DK 141333 B DK141333 B DK 141333B DK 297876A A DK297876A A DK 297876AA DK 297876 A DK297876 A DK 297876A DK 141333 B DK141333 B DK 141333B
- Authority
- DK
- Denmark
- Prior art keywords
- thieno
- tetrahydro
- pyridine
- formula
- hydroxy
- Prior art date
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- 150000003222 pyridines Chemical class 0.000 title description 2
- 238000004519 manufacturing process Methods 0.000 title 1
- 239000013078 crystal Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 12
- -1 6- (1-3-hydroxynaphthylmethyl) -4,5,6,7-tetrahydro-thieno- [2,3-c] pyridine Chemical compound 0.000 claims description 10
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 230000008018 melting Effects 0.000 claims description 5
- 238000002844 melting Methods 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- OJYDKYKQCVPTFG-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[3,2-c]pyridine Chemical class C1N=CC=C2SCCC21 OJYDKYKQCVPTFG-UHFFFAOYSA-N 0.000 claims description 3
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- DKASUYIOUPPQSY-UHFFFAOYSA-N 2,3,3a,4-tetrahydrothieno[2,3-c]pyridine Chemical class C1C=NC=C2SCCC21 DKASUYIOUPPQSY-UHFFFAOYSA-N 0.000 claims 2
- FKQKBMPNBGMDEB-UHFFFAOYSA-N 2,6-dichloro-4-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-ylmethyl)phenol Chemical compound C1=C(Cl)C(O)=C(Cl)C=C1CN1CC(C=CS2)=C2CC1 FKQKBMPNBGMDEB-UHFFFAOYSA-N 0.000 claims 1
- DDPDEZZCLVJUFJ-UHFFFAOYSA-N 2-(5,7-dihydro-4h-thieno[2,3-c]pyridin-6-ylmethyl)-4-methylphenol Chemical compound CC1=CC=C(O)C(CN2CC=3SC=CC=3CC2)=C1 DDPDEZZCLVJUFJ-UHFFFAOYSA-N 0.000 claims 1
- PHGWNHGNBZRXEA-UHFFFAOYSA-N 2-(5,7-dihydro-4h-thieno[2,3-c]pyridin-6-ylmethyl)-5-(dimethylamino)phenol Chemical compound OC1=CC(N(C)C)=CC=C1CN1CC(SC=C2)=C2CC1 PHGWNHGNBZRXEA-UHFFFAOYSA-N 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- 229930040373 Paraformaldehyde Natural products 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229920006324 polyoxymethylene Polymers 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 3
- 150000002989 phenols Chemical class 0.000 description 3
- NXXYKOUNUYWIHA-UHFFFAOYSA-N 2,6-Dimethylphenol Chemical compound CC1=CC=CC(C)=C1O NXXYKOUNUYWIHA-UHFFFAOYSA-N 0.000 description 2
- OGUWOLDNYOTRBO-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical class C1NCCC2=C1C=CS2 OGUWOLDNYOTRBO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 125000006619 (C1-C6) dialkylamino group Chemical group 0.000 description 1
- SZTBVHSMGGKHIV-UHFFFAOYSA-N 2,3-dichloro-6-(5,7-dihydro-4h-thieno[2,3-c]pyridin-6-ylmethyl)phenol Chemical compound C1=CC(Cl)=C(Cl)C(O)=C1CN1CC(SC=C2)=C2CC1 SZTBVHSMGGKHIV-UHFFFAOYSA-N 0.000 description 1
- OVBJBXNYOLGAHO-UHFFFAOYSA-N 2-(5,7-dihydro-4h-thieno[2,3-c]pyridin-6-ylmethyl)-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1CN1CC(SC=C2)=C2CC1 OVBJBXNYOLGAHO-UHFFFAOYSA-N 0.000 description 1
- XSXSHIKPBUVUIC-UHFFFAOYSA-N 2-(5,7-dihydro-4h-thieno[2,3-c]pyridin-6-ylmethyl)-6-propan-2-ylphenol Chemical compound CC(C)C1=CC=CC(CN2CC=3SC=CC=3CC2)=C1O XSXSHIKPBUVUIC-UHFFFAOYSA-N 0.000 description 1
- ARFZLYSRMCMIMR-UHFFFAOYSA-N 2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-ylmethyl)-4-fluorophenol Chemical compound OC1=CC=C(F)C=C1CN1CC(C=CS2)=C2CC1 ARFZLYSRMCMIMR-UHFFFAOYSA-N 0.000 description 1
- NWVVVCUDMGQYTL-UHFFFAOYSA-N 2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-ylmethyl)-4-methoxyphenol Chemical compound COC1=CC=C(O)C(CN2CC=3C=CSC=3CC2)=C1 NWVVVCUDMGQYTL-UHFFFAOYSA-N 0.000 description 1
- SVYMFEPXGHGQNG-UHFFFAOYSA-N 2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-ylmethyl)-4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1CN1CC(C=CS2)=C2CC1 SVYMFEPXGHGQNG-UHFFFAOYSA-N 0.000 description 1
- OCUQAUOYZMJSPM-UHFFFAOYSA-N 2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-ylmethyl)-6-methoxyphenol Chemical compound COC1=CC=CC(CN2CC=3C=CSC=3CC2)=C1O OCUQAUOYZMJSPM-UHFFFAOYSA-N 0.000 description 1
- LQKVSAZRTFKJBF-UHFFFAOYSA-N 2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-ylmethyl)-6-methylphenol Chemical compound CC1=CC=CC(CN2CC=3C=CSC=3CC2)=C1O LQKVSAZRTFKJBF-UHFFFAOYSA-N 0.000 description 1
- UVMIHYGDCXLPJP-UHFFFAOYSA-N 2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-ylmethyl)phenol Chemical compound OC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 UVMIHYGDCXLPJP-UHFFFAOYSA-N 0.000 description 1
- JWAZRIHNYRIHIV-UHFFFAOYSA-N 2-naphthol Chemical compound C1=CC=CC2=CC(O)=CC=C21 JWAZRIHNYRIHIV-UHFFFAOYSA-N 0.000 description 1
- DYSXAORFFOLJPL-UHFFFAOYSA-N 3-(5,7-dihydro-4h-thieno[2,3-c]pyridin-6-ylmethyl)-4-hydroxybenzonitrile Chemical compound OC1=CC=C(C#N)C=C1CN1CC(SC=C2)=C2CC1 DYSXAORFFOLJPL-UHFFFAOYSA-N 0.000 description 1
- HXNOEHIMWZDRTK-UHFFFAOYSA-N 4,5,6,7-tetrahydrothieno[2,3-c]pyridine Chemical compound C1NCCC2=C1SC=C2 HXNOEHIMWZDRTK-UHFFFAOYSA-N 0.000 description 1
- XBUVWBZNDZGRPM-UHFFFAOYSA-N 4-(5,7-dihydro-4h-thieno[2,3-c]pyridin-6-ylmethyl)-2,6-dimethylphenol Chemical compound CC1=C(O)C(C)=CC(CN2CC=3SC=CC=3CC2)=C1 XBUVWBZNDZGRPM-UHFFFAOYSA-N 0.000 description 1
- LTNBWFNJYMQXGS-UHFFFAOYSA-N 4-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-ylmethyl)-2,6-dimethylphenol Chemical compound CC1=C(O)C(C)=CC(CN2CC=3C=CSC=3CC2)=C1 LTNBWFNJYMQXGS-UHFFFAOYSA-N 0.000 description 1
- UAKQHKZGKWIGLO-UHFFFAOYSA-N 4-chloro-2-(5,7-dihydro-4h-thieno[2,3-c]pyridin-6-ylmethyl)phenol Chemical compound OC1=CC=C(Cl)C=C1CN1CC(SC=C2)=C2CC1 UAKQHKZGKWIGLO-UHFFFAOYSA-N 0.000 description 1
- DQTUGTIPLDAVEM-UHFFFAOYSA-N 4-chloro-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-ylmethyl)phenol Chemical compound OC1=CC=C(Cl)C=C1CN1CC(C=CS2)=C2CC1 DQTUGTIPLDAVEM-UHFFFAOYSA-N 0.000 description 1
- MFSORRKKXZZSPE-UHFFFAOYSA-N 4-chloro-2-[(7-methyl-5,7-dihydro-4h-thieno[2,3-c]pyridin-6-yl)methyl]phenol Chemical compound C1CC=2C=CSC=2C(C)N1CC1=CC(Cl)=CC=C1O MFSORRKKXZZSPE-UHFFFAOYSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 description 1
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 206010015856 Extrasystoles Diseases 0.000 description 1
- 238000006683 Mannich reaction Methods 0.000 description 1
- 208000000418 Premature Cardiac Complexes Diseases 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- AINBZKYUNWUTRE-UHFFFAOYSA-N ethanol;propan-2-ol Chemical compound CCO.CC(C)O AINBZKYUNWUTRE-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- QAXZWHGWYSJAEI-UHFFFAOYSA-N n,n-dimethylformamide;ethanol Chemical compound CCO.CN(C)C=O QAXZWHGWYSJAEI-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- SAALQYKUFCIMHR-UHFFFAOYSA-N propan-2-ol;2-propan-2-yloxypropane Chemical compound CC(C)O.CC(C)OC(C)C SAALQYKUFCIMHR-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
141333
Opfindelsen angår en særlig fremgangsmåde til fremstilling af hidtil ukendte tetrahydro-thienof3,2-c]pyridinderivater med formlen ^Vr2 _''~~N- CH,—i/ ^7 QUi 2Λ=^3 5 eller de isomere tetrahydro-thieno[2,3-c]pyridinderivater deraf med formlen OH r2
UQ- CH2-^S^r3 iIW
R1 hvori hydroxylgruppen OH findes i 2- eller 4-stillingen, R^-betegner et hydrogenatom eller en alkylgruppe med 1-6 carbonatnmer, 10 og R^ og R^ betegner hydrogen, halogen, en alkylgruppe med 1-6 carbonatomer eller en alkoxygruppe med 1-6 carbonato- mer, en di(C1_g-alkyl)aminogruppe eller en nitro-, cyano- eller acetamidogruppe, eller sammen med phenylkernen, 2 hvortil de er knyttet, danner en naphtylring, idet R og 3 15 R findes i 3-, 4-, 5- eller 6-stillingen, når OH findes i 2-stillingen, og findes i 3- og 5-stillingen samt er andet end hydrogen, når OH-gruppen findes it 4-stillingen.
De omhandlede forbindelser har værdifulde terapeutiske egenskaber, idet de har antiinflammatorisk virkning, virk-20 ning som antiarrhytmika samt inhiberende virkning på blod-pladeaggregation. Forbindelserne kan derfor let anvendes til behandling af forskellige inflammationstilstande (kronisk og degenerativ rheumatisme, stomatologi, traumatologi, etc.), til behandling af forstyrrelseri hjerterytmen 141333 2 (tachycardi, extrasystoler) samt til behandling af forstyrrelser i det cerebrale og perifere kredsløb.
I beskrivelsen til dansk patent nr. 136.651 er visse 4,5,6,7-tetrahydro-thieno[3,2~c]pyridinderivater allerede blevet be-5 skrevet tilligemed en fremgangsmåde til fremstilling deraf.
Den nævnte fremgangsmåde omfatter kondensation af bl.a. en forbindelse med formlen 2' hvori R er hydrogen eller halogen, med bl.a. et halogenid med 10 formlen Hal-CH2-R, hvori Hal betegner et halogenatom, og R betegner en phenylgruppe, der eventuelt er substitueret med 1-3 halogenatomer, alkylgrupper med 1-6 carbonatomer, alkoxygrupper med 1-6 carbonatomer, nitrogrupper eller hydroxygrupper, til opnåelse af et pyridiniumsalt med formlen
15 R2' Xj3l_CH2-R,HaP
2'
hvori R , R og Hal har den ovennævnte betydning, og efterfølgende hydrogenering af nævnte pyridiniumsalt til opnåelse af et derivat med formlen I
JIjO-ch -r 2' Δ
R
ΛΛ 2 1 hvori R og R har den ovennævnte betydning. 4,5,6,7-tetra= hydro-thieno[2,3-c] pyridinderivater har også været fremstillet ved en analog fremgangsmåde (beskrivelsen til dansk patentansøgning nr. 2799/76). Denne fremgangsmåde er imidlertid dyr og kompliceret, da den kræver talrige vanskelige procedurer.
2 5
Endvidere gør anvendelsen af denne fremstillingsproces det 3 141333 vanskeligt at opnå derivater, som til nitrogenatomet har knyttet en benzylgruppe, der bærer en hydroxyIgruppe i 2-eller 4-stillingen. Til opnåelse af derivater af en sådan type ifølge nævnte fremgangsmåde er det i virkeligheden 5 nødvendigt at gå frem via det methoxylerede derivat, som derpå hydrolyseres.
Det methoxylerede derivat vil kunne fremstilles i overensstemmelse med nedenstående reaktionsskema (i tilfælde af derivater af typen[3,2-c]): R1 OCH3 rsW /tvr2 10 + hvilken reaktion fører til pyridiniumderivater med formlen
Hal9 som man kan hydrogenere til opnåelse af forbindelser med formlen R °CH3 iXi—&· 12 3 i hvilke formler R , R og R har de ovenfor anførte betydninger, som derefter kan demethyleres, f.eks. ved hjælp af 48% hydrogenbromidsyre under tilbagesvaling eller ved hjælp af pyridiniumchlorid ved 150-250°C eller ved hjælp af bortri= 20 bromid ved omgivelsernes temperatur.
En sådan fremgangsmåde ville imidlertid være kostbar (som følge af de tre trin), og den ville føre til et meget lavt 141333 4 udbytte som følge af de lave udbytter ved demethyleringen/ især når methoxygruppen befinder sig i 2-stillingen på ben= zylringen.
Den foreliggende opfindelse tager derfor sigte på at angive 5 en enklere fremgangsmåde til i højt udbytte at fremstille derivater med formlen la og isomere deraf med formlen Ib, i hvilke phenylkernen bærer en hydroxygruppe i 2- eller 4-stillingen.
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at 10 et tetrahydro-thieno[3,2-c]pyridinderivat med formlen gO^ (Ila> eller dets isomere tetrahydro[2,3-cIpyridin, med formlen di« R1 hvori R"*· har de ovenfor anførte betydninger, omsættes med 15 formaldehyd H-CHO og en phenol med formlen
OH
éc* (m) 2 3 hvori R og R har de ovenfor anførte betydninger, til opnåelse af det ønskede derivat med formlen la eller Ib.
Reaktionen (af Mannichtypen) finder sted ved den ene af 20 phenolens orthostillinger, når denne er fri. Når begge orthostillingerne er optaget, finder reaktionen sted ved parastillingen.
5 141333 I tilfælde af phenoler, hvori mindst en af orthostillinger-ne i forhold til OH-gruppen er fri, finder Mannichreaktio-nen således sted ved nævnte frie orthostilling, f.eks.:
OK
l / 2-(^R
|p-|^m r3
^s^A.Ri S
2 3 5 idet grupperne R og R valgfrit optager 3-, 4-, 5- eller 6-stillingen i derivatet med formlen la eller Ib.
Den samme reaktion finder sted med usubstitueret phenol og med polycykliske phenoler, såsom eksempelvis (3-naphthol.
2
I tilfælde af phenoler, som bærer begge substituenterne R
3 10 og R i orthostillingen til OH-gruppen, finder reaktionen sted ved parastillingen, f.eks.: 2 /r2 gO1·"* CHUO'"·^'
Kondensationsreaktionen ifølge opfindelsen udføres hensigtsmæssigt i et medium bestående af et organisk opløs-15 ningsmiddel, såsom ethanol, propanol eller dioxan. Reaktionen udføres hensigtsmæssigt i varmen ved en temperatur mellem 50° og kogepunktet for det benyttede opløsningsmiddel, idet de bedste resultater opnås ved temperaturer omkring 80°C.
20 Det foretrækkes at udføre reaktionen under konstant omrøring i løbet af et tidsrum på 2 til 20 timer.
141333 6
Formaldehyd eller de forskellige polymerisationsprodukter deraf, såsom polyoxymethylen, kan anvendes til reaktionen.
Rensning af det ønskede derivat udføres enten ved rekry-stallisation fra et organisk opløsningsmiddel eller efter 5 omdannelse til et salt, ved vaskning, tørring og eventuelt rekrystallisation fra et organisk opløsningsmiddel.
De følgende eksempler illustrerer nærmere fremgangsmåden ifølge opfindelsen.
Eksempel 1 10 Fremstilling af 5-(3,5-dimethyl-4-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin.
En blanding af 4,5,6,7-tetrahydro-thieno[3,2-c]pyridin (6,1 g, 44 mmol), 2,6-dimethyl-phenol (5,4 g, 44 mmol), polyoxymethylen (2,7 g, 90 mmol) og dioxan (50 ml) omrøres 15 ved 80°C i tre timer. Efter inddampning i vakuum rekry-stalliseres resten fra ethanol-isopropanol (smeltepunkt 150°C, udbytte 48%).
Eksempel 2
Fremstilling af 5-(2-hydroxy-5-nitro-benzyl)-6-methyl-20 4,5,6,7-tetrahydro-thieno[3,2-c]pyridin.
En blanding af 6-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]= pyridin (6,3 g, 41 mmol), p-nitro-phenol (5,7 g, 41 mmol), polyoxymethylen (2,5 g, 83 mmol) og dioxan (50 ml) ‘omrøres ved 80°C i fire timer. Efter inddampning i vakuum opløses 25 resten i ether og behandles med 0,5 ækvivalent oxalsyre i ethanolopløsning. Det resulterende semioxalat filtreres, vaskes med kogende methanol-vand (1:3), filtreres atter og tørres (smeltepunkt 214°C, udbytte 27%).
7 141333
Eksempel 3
Fremstilling af 6-(2-hydroxy-5-chlor-benzyl)-7-methyl- 4,5,6,7-tetrahydro-thieno[2,3-c]pyridin.
En blanding af 7-methyl-4,5,6,7-tetrahydro-thieno[2,3-c]= 5 pyridin (6,0 g, 39,2 mmol), p-chlorphenol (5,05 g, 39,2 mmol), polyoxymethylen (2,36 g, 78,5 mmol) og dioxan (70 ml) omrøres ved 80°C i 15 timer. Efter inddampning i vakuum optages resten i 2N saltsyre. Den vandige fase eks-traheres med ether, gøres basisk med koncentreret ammoniak 10 og ekstraheres med methylenchlorid. De organiske ekstrakter vaskes med vand, tørres over natriumsulfat og inddamp-pes i vakuum. Resten behandles med 0,5 ækvivalent oxalsyre i ethanolopløsning. Det resulterende semioxalat filtreres og rekrystalliseres fra ethanol-dimethylformamid (smelte-15 punkt 270°C, udbytte 38%).
Eksempel 4
Fremstilling af 6-(2-hydroxy-5-cyano-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin.
En blanding af 4,5,6,7-tetrahydro-thieno[2,3-c]pyridin 20 (1 g, 7,2 mmol), p-cyano-phenol (95% renhed, 0,9 g, 7,2 mmol), polyoxymethylen (0,43 g, 14,4 mmol) dg dioxan (20 ml) omrøres ved 80°C i 4 timer. Efter inddampning i vakuum optages resten i 2N saltsyre. Den vandige fase ekstraheres med ether, gøres basisk med koncentreret ammoniak 25 og ekstraheres med methylenchlorid. De organiske ekstrakter vaskes med vand, tørres over natriumsulfat og inddampes i vakuum. Resten rekrystalliseres fra isopropylether-isopropanol (smeltepunkt 134°C, udbytte 23%).
*
Under anvendelse af analoge med de i de foregående eksem-30 pier beskrevne procedurer opnås følgende forbindelser: 141333 8
Eksempel 5 5-(2-hydroxy-5-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno-[3,2-c]pyridin.
Hvide krystaller, smeltepunkt 90°C.
5 Eksempel 6 5-(2-hydroxy-5-nitro-benzy1)-4,5,6,7-tetrahydro-thieno-[3,2-c]pyridin.
Gule krystaller, smeltepunkt 160°C.
Eksempel 7 10 5-(2-hydroxy-3-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno- [3,2-c]pyridin.
Hvide krystaller, smeltepunkt 84°C.
Eksempel 8 5-(5-chlor-2-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno-15 [3,2-cjpyridin.
Hvide krystaller, smeltepunkt 82-85°C.
Eksempel 9 5-(5-chlor-2-hydroxy-behzyl)-6-methyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin, semioxalat.
20 Hvide krystaller, smeltepunkt 200°C.
Eksempel 10 5-(5-fluor-2-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno-[3,2-c]pyridin.
Bleggule krystaller, smeltepunkt 92°C.
25 Eksempel 11 5-o-hydroxybenzyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridin, semioxalat.
Hvide krystaller, smeltepunkt 216°C.
9 141333
Eksempel 12 5- (2-hydroxy-3-methyl-benzyl)-4,5,6,7-tetrahydro-thieno-[3,2-c]pyridin, semioxalat, semihydrat.
Hvide krystaller, smeltepunkt 198°C.
5 Eksempel 13 5- (3-acetamido-2-hydroxy-benzyl)-4,5,6,6-thieno[3,2-c]py= ridin.
Hvide krystaller, smeltepunkt 154°C.
Eksempel 14 10 6-(5-chlor-2-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno- [2,3-c]pyridin.
Hvide krystaller, smeltepunkt 222°C.
Eksempel 15 6- (3,4-dichlor-2-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno- 15 [2,3-c]pyridin.
Hvide krystaller, smeltepunkt 153°C.
Eksempel 16 6-(2-hydroxy-5-nitro-benzyl)-4,5,6,7-tetrahydro-thieno-[2,3-c]pyridin.
20 Gule krystaller, smeltepunkt 159°C.
Eksempel 17 6-(3,5-dimethyl-4-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin.
Elfenbensfarvede krystaller, smeltepunkt 118°C.
25 Eksempel 18 6-(2-hydroxy-3-isopropyl-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin.
Meget blege, gule krystaller, smeltepunkt 101°C.
Claims (4)
141333 ίο Eksempel 19 6-(2-hydroxy-5-methyl-benzyl)-4,5,6,7-tetrahydro-thieno-[2,3-c]pyridin, Meget blege, gule krystaller, smeltepunkt 196°C.
5 Eksempel 20 6-(4-dimethylamino-2-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno [2,3-c]pyridin. Lyserøde krystaller, smeltepunkt 140°C. Eksempel 21 10 6-Q-hydroxybenzyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin. Beige krystaller, smeltepunkt 98°C. Eksempel 22 6-(1-3-hydroxynaphthyl-methyl)-4,5,6,7-tetrahydro—thieno-[2,3-c]pyridin.
15 Bleggule krystaller, smeltepunkt 150°C. Eksempel 23 5-(3,5-dichlor-4-hydroxy-benzyl)-4,5,6,7-tetrahydro-thieno [3,2-c]pyridin. Hvide krystaller, smeltepunkt 170°C.
20 Patentkrav. Fremgangsmåde til fremstilling af tetrahydro-thieno[3,2-c] -pyridinderivater med formlen OH prr eller de isomere tetrahydro-thieno[2,3-c]pyridinderivater 25 deraf med formlen 141333 OH UQ-ch2 -QQ hvori hydroxygruppen findes i 2-eller 4-stillingen, betegner et hydrogenatom eller en alkylgruppe med 1-6 carbonatomer, 2 3 og R og R betegner hydrogen,halogen,en alkylgruppe med 1-6 5 carbonatomer eller en alkoxygruppe med 1-6 carbonatomer, en di(C1_g-alkyl)aminogruppe eller en nitro-, cyano- eller acetamidogruppe, eller sammen med phenylkernen, hvor- 2 3 til de er knyttet, danner en naphtylring, idet R og R findes i 3-, 4-, 5-, eller 6-stillingen, når OH findes i 10 2-stillingen, og findes i 3- og 5-stillingen samt er andet end hydrogen, når OH-gruppen findes i 4-stillingen, kendetegnet ved, at et tetrahydro-thieno[3,2-c]pyri= dinderivat med formlen g(X »· 15 eller dets isomere tetrahydrothieno[2,3-c]pyridin, med formlen ΐζλΛ R1 i hvori R har de ovenfor anførte betydninger, omsættes med formaldehyd H-CHO og en phenol med formlen
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7521549A FR2317303A1 (fr) | 1975-07-09 | 1975-07-09 | Procede de preparation de derives de la tetrahydrothieno (3,2-c) et (2,3-c) pyridine |
| FR7521549 | 1975-07-09 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK297876A DK297876A (da) | 1977-01-10 |
| DK141333B true DK141333B (da) | 1980-02-25 |
| DK141333C DK141333C (da) | 1980-08-25 |
Family
ID=9157715
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK297876AA DK141333B (da) | 1975-07-09 | 1976-07-01 | Fremgangsmåde til fremstilling af tetrahydro-thieno(3,2-c)- eller-(2,3-c)pyridinderivater. |
Country Status (26)
| Country | Link |
|---|---|
| JP (1) | JPS5236691A (da) |
| AR (1) | AR211019A1 (da) |
| AT (1) | AT348526B (da) |
| BE (1) | BE843822A (da) |
| CA (1) | CA1071634A (da) |
| CH (1) | CH609349A5 (da) |
| DD (1) | DD125081A5 (da) |
| DE (1) | DE2630474A1 (da) |
| DK (1) | DK141333B (da) |
| ES (1) | ES448404A1 (da) |
| FR (1) | FR2317303A1 (da) |
| GB (1) | GB1544093A (da) |
| GR (1) | GR59812B (da) |
| HU (1) | HU172280B (da) |
| IE (1) | IE42821B1 (da) |
| IL (1) | IL49641A (da) |
| LU (1) | LU74674A1 (da) |
| MX (1) | MX3224E (da) |
| NL (1) | NL7605362A (da) |
| PH (1) | PH12311A (da) |
| PL (1) | PL100685B1 (da) |
| PT (1) | PT65072B (da) |
| SE (1) | SE421699B (da) |
| SU (1) | SU628819A3 (da) |
| YU (1) | YU40137B (da) |
| ZA (1) | ZA763219B (da) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5665315A (en) * | 1979-11-02 | 1981-06-03 | Nec Corp | Magnetic recording and inspecting system |
| DE3736664A1 (de) * | 1987-10-29 | 1989-05-11 | Boehringer Ingelheim Kg | Tetrahydro-furo- und -thieno(2,3-c)pyridine, ihre verwendung als arzneimittel und verfahren zu ihrer herstellung |
| NZ233654A (en) * | 1989-05-18 | 1993-02-25 | Bristol Myers Squibb Co | 2-aminomethyl-5-aminophenol derivatives; hair dye compositions containing them |
-
1975
- 1975-07-09 FR FR7521549A patent/FR2317303A1/fr active Granted
-
1976
- 1976-03-31 LU LU74674A patent/LU74674A1/xx unknown
- 1976-04-01 CH CH404576A patent/CH609349A5/xx not_active IP Right Cessation
- 1976-04-21 GR GR50593A patent/GR59812B/el unknown
- 1976-04-23 YU YU1030/76A patent/YU40137B/xx unknown
- 1976-05-06 PT PT65072A patent/PT65072B/pt unknown
- 1976-05-19 NL NL7605362A patent/NL7605362A/xx not_active Application Discontinuation
- 1976-05-21 IE IE1079/76A patent/IE42821B1/en unknown
- 1976-05-24 IL IL49641A patent/IL49641A/xx unknown
- 1976-05-31 ES ES448404A patent/ES448404A1/es not_active Expired
- 1976-06-01 ZA ZA763219A patent/ZA763219B/xx unknown
- 1976-06-03 AR AR263501A patent/AR211019A1/es active
- 1976-06-09 SU SU762366005A patent/SU628819A3/ru active
- 1976-06-10 CA CA254,573A patent/CA1071634A/en not_active Expired
- 1976-06-16 MX MX000320U patent/MX3224E/es unknown
- 1976-07-01 PH PH7618641A patent/PH12311A/en unknown
- 1976-07-01 DK DK297876AA patent/DK141333B/da not_active IP Right Cessation
- 1976-07-05 AT AT489876A patent/AT348526B/de not_active IP Right Cessation
- 1976-07-06 BE BE168664A patent/BE843822A/xx not_active IP Right Cessation
- 1976-07-07 SE SE7607762A patent/SE421699B/xx not_active IP Right Cessation
- 1976-07-07 DE DE19762630474 patent/DE2630474A1/de active Pending
- 1976-07-07 DD DD193745A patent/DD125081A5/xx unknown
- 1976-07-08 GB GB28511/76A patent/GB1544093A/en not_active Expired
- 1976-07-08 PL PL1976191016A patent/PL100685B1/pl unknown
- 1976-07-08 JP JP51081441A patent/JPS5236691A/ja active Granted
- 1976-07-09 HU HU76PA00001255A patent/HU172280B/hu unknown
Also Published As
| Publication number | Publication date |
|---|---|
| PL100685B1 (pl) | 1978-10-31 |
| MX3224E (es) | 1980-07-28 |
| DK141333C (da) | 1980-08-25 |
| CH609349A5 (en) | 1979-02-28 |
| DK297876A (da) | 1977-01-10 |
| IE42821L (en) | 1977-01-09 |
| FR2317303B1 (da) | 1977-12-16 |
| AU1568676A (en) | 1977-03-31 |
| FR2317303A1 (fr) | 1977-02-04 |
| HU172280B (hu) | 1978-07-28 |
| NL7605362A (nl) | 1977-01-11 |
| YU103076A (en) | 1982-02-28 |
| CA1071634A (en) | 1980-02-12 |
| ATA489876A (de) | 1978-07-15 |
| ZA763219B (en) | 1977-05-25 |
| PT65072B (fr) | 1977-09-13 |
| YU40137B (en) | 1985-08-31 |
| PH12311A (en) | 1979-01-16 |
| AR211019A1 (es) | 1977-10-14 |
| IE42821B1 (en) | 1980-10-22 |
| SE421699B (sv) | 1982-01-25 |
| DE2630474A1 (de) | 1977-01-13 |
| IL49641A (en) | 1978-08-31 |
| AT348526B (de) | 1979-02-26 |
| PT65072A (fr) | 1976-06-01 |
| BE843822A (fr) | 1977-01-06 |
| GR59812B (en) | 1978-03-01 |
| JPS5310077B2 (da) | 1978-04-11 |
| IL49641A0 (en) | 1976-07-30 |
| JPS5236691A (en) | 1977-03-22 |
| SE7607762L (sv) | 1977-01-10 |
| ES448404A1 (es) | 1977-07-01 |
| DD125081A5 (da) | 1977-03-30 |
| LU74674A1 (da) | 1976-09-01 |
| SU628819A3 (ru) | 1978-10-15 |
| GB1544093A (en) | 1979-04-11 |
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