NO155666B - Fremgangsmaate for fremstilling av 5,6,7,7a-tetrahydro-4h-thieno-(3,2-c)-pyridin-2-on-derivater. - Google Patents
Fremgangsmaate for fremstilling av 5,6,7,7a-tetrahydro-4h-thieno-(3,2-c)-pyridin-2-on-derivater. Download PDFInfo
- Publication number
- NO155666B NO155666B NO814056A NO814056A NO155666B NO 155666 B NO155666 B NO 155666B NO 814056 A NO814056 A NO 814056A NO 814056 A NO814056 A NO 814056A NO 155666 B NO155666 B NO 155666B
- Authority
- NO
- Norway
- Prior art keywords
- thieno
- tetrahydro
- pyridin
- gaseous hydrogen
- derivatives
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- PYQVFGJHIWJNFS-UHFFFAOYSA-N 5,6,7,7a-tetrahydro-4h-thieno[3,2-c]pyridin-2-one Chemical class C1CNCC2=CC(=O)SC21 PYQVFGJHIWJNFS-UHFFFAOYSA-N 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 7
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 239000003960 organic solvent Substances 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
- 150000007513 acids Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 235000005985 organic acids Nutrition 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- 238000005481 NMR spectroscopy Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000013078 crystal Substances 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- -1 5-(2-chlorobenzyl)-5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridine Chemical compound 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- DJZQIXWGIZIETJ-UHFFFAOYSA-N 2-Oxoticlopidine Chemical compound ClC1=CC=CC=C1CN1CC2=CC(=O)SC2CC1 DJZQIXWGIZIETJ-UHFFFAOYSA-N 0.000 description 1
- BDSNMIVGSVEKMH-UHFFFAOYSA-N 2-[(2-oxo-4,6,7,7a-tetrahydrothieno[3,2-c]pyridin-5-yl)methyl]benzonitrile Chemical compound C1C2=CC(=O)SC2CCN1CC1=CC=CC=C1C#N BDSNMIVGSVEKMH-UHFFFAOYSA-N 0.000 description 1
- QAVVHZPFNXYQAO-UHFFFAOYSA-N 2-[1-[(2-chlorophenyl)methyl]-4-oxopiperidin-3-yl]acetic acid hydrochloride Chemical compound Cl.C1CC(=O)C(CC(=O)O)CN1CC1=CC=CC=C1Cl QAVVHZPFNXYQAO-UHFFFAOYSA-N 0.000 description 1
- BCHVUNIQSDWWJG-UHFFFAOYSA-N 5-[(2-bromophenyl)methyl]-4,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2-one Chemical compound BrC1=CC=CC=C1CN1CC2=CC(=O)SC2CC1 BCHVUNIQSDWWJG-UHFFFAOYSA-N 0.000 description 1
- PGQKLKQLJNSJRI-UHFFFAOYSA-N 5-[(2-nitrophenyl)methyl]-4,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2-one Chemical compound [O-][N+](=O)C1=CC=CC=C1CN1CC2=CC(=O)SC2CC1 PGQKLKQLJNSJRI-UHFFFAOYSA-N 0.000 description 1
- TWROMOHFQXTXIE-UHFFFAOYSA-N 5-[1-(2-chlorophenyl)ethyl]-4,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2-one Chemical compound C1CC2SC(=O)C=C2CN1C(C)C1=CC=CC=C1Cl TWROMOHFQXTXIE-UHFFFAOYSA-N 0.000 description 1
- LFHGEKPUPGEFCL-UHFFFAOYSA-N 5-[1-(2-chlorophenyl)propyl]-4,6,7,7a-tetrahydrothieno[3,2-c]pyridin-2-one Chemical compound C1CC2SC(=O)C=C2CN1C(CC)C1=CC=CC=C1Cl LFHGEKPUPGEFCL-UHFFFAOYSA-N 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical group C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000001816 cooling 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
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- QMEZUZOCLYUADC-UHFFFAOYSA-N hydrate;dihydrochloride Chemical compound O.Cl.Cl QMEZUZOCLYUADC-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- 150000004715 keto acids Chemical class 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000010183 spectrum analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical class C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
- CWERGRDVMFNCDR-UHFFFAOYSA-N thioglycolic acid Chemical class OC(=O)CS CWERGRDVMFNCDR-UHFFFAOYSA-N 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
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/74—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (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
Denne oppfinnelse angår en ny fremgangsmåte for fremstilling av 5 , 6 , 7, 7a-tetrahydro-4H-thieno- (3, 2-c)-pyridin-2-on-derivater.
De 5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin-2-on-derivater som den foreliggende oppfinnelse angår, er forbindelser av den generelle formel:
hvor R er et hydrogenatom eller en fenylgruppe som eventuelt kan være substituert med minst ett halogenatom eller minst én C^-C^j-alkylgruppe, nitrogruppe eller cyanogruppe, R' er et hydrogenatom eller en lavere alkylgruppe, og n er 0, 1, 2 eller 4, samt syreaddisjonssaltene av disse forbindelser med mineralsyrer og organiske syrer.
Disse forbindelser av formel I har anti-blodplate-aggregerende egenskaper og antitrombotiske egenskaper og er gjenstand for norsk patentsøknad nr. 814055.
De omfattes likeledes av en generell formel som er gitt i franske patentskrifter nr. 7303503 og 7524486 i følgende tautomere form:
hvor R, R<1> og n har de ovenfor angitte betydninger.
Imidlertid er ingen av forbindelsene (I) spesifikt beskrevet i disse.
Det er fra fransk patentskrift nr. 2338703 kjent en fremgangsmåte for fremstilling av thieno-pyridin-derivater, hvor en cyklisering av thiofenringen foretas i to trinn, idet det startes med et piperidonderivat som først konden-seres med et mercaptoeddiksyrederivat og deretter ringsluttes ved hjelp av en base i et organisk oppløsningsmiddel.
Ved hjelp av oppfinnelsen tilveiebringes der en ny og enklere fremgangsmåte for fremstilling av forbindelser av den generelle formel I, ved hvilken en forbindelse av den generelle formel:
hvor R, R' og n har de ovenfor angitte betydninger, og R" er et hydrogenatom eller en alkylgruppe inneholdende inntil 4 carbonatomer, behandles med gassformig hydrogenklorid og gassformig hydrogensulfid i et organisk oppløsningsmiddel-.
Innvirkningen av det gassformige hydrogenklorid og det gassformige hydrogensulfid kan avstedkommes samtidig ved hjelp av en blanding av de to gasser, hvilket foretrekkes, eller ved separat innvirkning av hver gass.
Reaksjonen utføres i et organisk oppløsningsmiddel, f.eks. en lavere alkanol, såsom methanol eller ethanol, eller en lavere carboxylsyre, såsom eddiksyre eller propionsyre, eller i en blanding av disse oppløsningsmidler. ,
Reaksjonen kan utføres ved en temperatur fra romtem- , peratur til koketemperaturen for det anvendte oppløsnings-middel .
Keto-syrene og keto-esterne av den generelle formel II kan fremstilles ved en fremgangsmåte analog med den som beskrives i publisert japansk patentsøknad Kokai nr. 79 98 771 i navnet Tokyo Koho, som det er referert til i Chemical Abstracts, 92, 41773x/1980, hva angår frem-stillingen av forbindelser av den generelle formel II i hvilken R<1> er hydrogen, R er en fenylgruppe og n er 1 eller 2.
De følgende eksempler illustrerer oppfinnelsen. Struk-turen av de fremstilte forbindelser ble bekreftet ved mikro-analyse, spektralanalyse i det infrarøde område og analyse med hensyn til kjernemagnetisk resonans.
Eksempel 1
5-(2-klorbenzyl)-5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin ( formel I; R = 2- C1. C H4; r' = H; n = 1) .
a) Fremstilling av methyl-[l-(2-klorbenzyl)-4-oxo-piperid-3- yl]- acetat
En oppløsning av 100 g (0,355 mol) ethyl-[l-(2-klor-benzyl) -4-oxopiperid-3-yl] -carboxyla.t (se J.P. Maffrand og D. Frehel, Bull. Soc. Chim. France, (1-2), 11-48/1978)
i 400 ml 1,2-dimethoxyethan tilsettes dråpevis til en blanding av 17,04 g (0,355 mol) natriumhydrid (50%-ig sus-pensjon) i 250 ml 1,2-dimethoxyethan. Reaksjonsblandingen omrøres ved romtemperatur i 30 minutter, hvoretter en blanding av 59,28 g (0,355 mol) ethylbromacetat i 250 ml 1,2-dimethoxyethan tilsettes dråpevis.
Reaksjonsblandingen omrøres ved romtemperatur i 2 timer, og den dannede utfeining frafiltreres og vaskes med diethyléther. Filtratet inndampes i vakuum. Inndampnings-residuet tas opp i vann og ekstraheres med methylenklorid. De organiske ekstrakter vaskes med vann, tørres over vannfritt natriumsulfat og filtreres gjennom et skikt, av kisel-syre. Filtratet inndampes i vakuum. De 12 3,2 g gul harpiks som oppnåes, oppløses i 850 ml 6N saltsyre, og oppløsningen kokes med tilbakeløpskjøling under nitrogenatmosfære i 4 timer. Etter avkjøling konsentreres reaksjonsblandingen under vakuum, og vann tilsettes, hvoretter det foretas ekstraksjon med diethyléther. De vandige faser gjøres svakt basiske ved tilsetning av natriumcarbonat og innstilles deretter på pH ca. 4 ved tilsetning av eddiksyre. De ekstraheres så med methylenklorid. De organiske faser vaskes med vann, tørres med vannfritt natriumsulfat og inndampes til tørrhet. Det 9 3,8 g erholdteharpiksprodukt oppløses i aceton og behandles med en etheroppløsning av gassformig hydrogenklorid. Det erholdte [1-(2-klorbenzyl)-4-oxopiperid-3-yl]-eddiksyre-hydroklorid frafiltreres, vaskes med aceton og deretter med diethyléther og tørres under vakuum. Denne forbindelse er-holdes i et utbytte av 64% i form av hvite krystaller som spaltes ved ca. 180°C. IR (KBr) : "0 CO = 1728 cm"<1>.
En oppløsning av 30 g av dette hydroklorid i 300 ml methanol mettet med gassformig hydrogenklorid omrøres ved romtemperatur i 3 timer. Reaksjonsblandingen inndampes deretter under vakuum ved temperatur under 5 0°C, og residuet helles over i vann, gjøres basisk ved tilsetning av natrium-bicarbonat og ekstraheres med methylenklorid. De organiske ekstrakter vaskes med vann, tørres med vannfritt natriumsulfat og inndampes til tørrhet. Den erholdte gule harpiks anvendes som sådan, uten ytterligere rensning, i det neste trinn. IR (film) CO = 1720 cm"<1>; NMR (CDC13) = 7,05 -
7,65 (m,4H); 3,72 (s,2H); 3,62 (s,3H).
b) 5-(2-klorbenzyl)-5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin- 2- on
Strømmer av gassformig hydrogenklorid og gassformig hydrogensulfid bobles inn i en til 85°C oppvarmet oppløs-ning av 4,5 g (0,0152 mol) av keto-esteren erholdt under punkt a) ovenfor i 45 ml eddiksyre. Reaksjonsblandingen konsentreres deretter under vakuum, og residuet tas opp i vann, innstilles på basisk pH ved tilsetning av natriumbi-carbonat og ekstraheres med methylenklorid. Ekstraktene vaskes med vann, tørres med vannfritt natriumsulfat og inndampes til tørrhet. De erholdte 3,6 g gul olje (utbytte: 86% av det teoretiske) overføres til oxalatet ved tilsetning av en oppløsning av oxalsyre i aceton. Smeltepunkt 170°C etter omkrystallisering fra ethanol. IR (KBr):^ Co = 1660 cm<-1 >(stor).
Etter utfeining fra aceton undergår det tilsvarende hydroklorid-hemihydrat spaltning ved ca. 180°C.
Etter omkrystallisering fra ethanol smelter den tilsvarende frie base ved 73 - 74,5°C. NMR (CDC1 ) = 7,1 -7,6 (m,4H) ; 6,2 (s,lH); 4,2 - 4,7 m, 1H) ; 3,9 (s,2H); 1,5 - 4,2 (m,6H).
Eksempler 2- 9
. De følgende forbindelser ble fremstilt på samme måte som beskrevet i eksempel 1: Derivat 2: 5-Benz<y>l-5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin-2-on formel (I) (R = CgH ; R<1> = H; n = 1)
maleat: beige krystaller; smeltepunkt 132 - 134°C(omkrystalli-sert fra isopropanol)
IR (KBr):V CO: 1680 cm"<1>
base: NMR (CDC13): 7,25 (m,5H); 5,90 (s,lH); 3,60 (s,2H). Derivat 3; 5-(4-klorbenzyl)-3,6,7,7a-tetrahydro-4H-thieno-(3, 2-c)-pyridin-2-on
formel (I) (R = 4-Ch-C,H.; R' = H; n = 1)
maleat: beige krystaller, smeltepunkt 158 - 160 oC (omkrystalli-sert fra ethanol)
IR (KBr):* CO = 1680 era"1 ;base: NMR (CDC13): 7,30 (m,4H); 6,0 (s,lH); 3,50 (s,2H). Derivat 4: 5-(2-methylbenzyl)-5,6,7,7a-tetrahydro-4H-thieno, (3,2-c)-pyridin-2-on ;formel (I) (R = 2-CH3~C6H4; R' = H; n = 1) ;oxalat: beige krystaller; smeltepunkt 195 - 197°C (omkrystalli-sert fra metha.no 1) ;IR (KBr):v CO = 1690 cm"<1>;base: NMR (CDC13): 7,10 (s,4H); 5,90 (s,lH); 3,55 (s,2H); 2 , 30 (s,3H) . ;Derivat 5: 5-[1-(2-klorfenyl)-ethyl]-5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin-2-on ;formel (I) (R = 2-Cl-CgH4; R' = CH3; n = 1) ;hydroklorid: gule krystaller; smeltepunkt 140 - 142°C. ;IR (KBr):V CO = 1690 cm"<1>;base: NMR (CDC13): 7,30 (m,4H); 6,05; 5,95 (2s,lH); (2 diastereoisomere). ;Derivat 6: 5-[ 1-(2-klorfenyl)-propyl]-5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin-2-on ;formel (I) (R = 2-Cl-C,_H. ; R' = C~Hr ; n = 1) ;hydroklorid: beige krystaller, smeltepunkt 124 - 126 oC. ;IR (KBR) : v* CO = 1690 cm"<1>
base: NMR (CDC13): 7,30 (m,4H); 6,05; 5,90 (2s,lH)
(2 diastereoisomere).
Derivat 7: 5-(2-cyanobenzyl)-5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin-2-on
formel (I) (R = 2-Cl-CgH^ R' = H; n = 1)
oxalat: beige krystaller; smeltepunkt 176 - 178 C (omkry-stallisert fra acetonitril)
IR (KBR) : ^ CO = 1700 cm"<1>; >/ CN = 2210 cm"<1>
base: NMR (CDC13): 7,50 (m,4H; 6,00 (s,lH); 3,80 (s,2H).
Derivat 8: 5-(2-nitrobenzyl)-5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin-2-on
formel (I) (R = 2-N02"C6H4; R' = H; n = 1)
oxalat: beige krystaller; smeltepunkt 186 - 188°C (omkry-
stallisert fra isopropanol-ethanol)
IR: v CO = 1685 cm"<1>
base: NMR (CDC13): 7,50 (m,4H); 5,95 (s,lH); 3,90 (s,2H).
Derivat 9: 5-(2-brombenzyl)-5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin-2-on
formel (I) (R = 2-Br-CgHj ; R' = H ; n = 1)
oxalat: beige krystaller; smeltepunkt 151 - 153°C (omkry-
stallisert fra isopropanol)
IR (KBr): V CO = 1690 cm"<1>
base: (CDC13): 7,30 (m,4H); 5,95 (s,lH); 3,75 (s,2H).
Claims (2)
1. Fremgangsmåte for fremstilling av 5,6,7,7a-tetrahydro-4H-thieno-(3,2-c)-pyridin-2-on-derivater av den generelle formel:
hvor R er et hydrogenatom eller en fenylgruppe som eventuelt kan være substituert med minst ett halogenatom eller minst én C^-C^-alkylgruppe, nitrogruppe eller cyanogruppe, R' er et hydrogenatom eller en lavere alkylgruppe, og n er 0, 1, 2 eller 4, samt syreaddisjonssaltene av disse forbindelser med mineralsyrer og organiske syrer,
karakterisert ved at en forbindelse av den generelle formel:
hvor R, R' og n har de ovenfor angitte betydninger, og R" er et hydrogenatom eller en alkylgruppe inneholdende inntil 4 carbonatomer, behandles med gassformig hydrogenklorid og gassformig hydrogensulfid i et organisk oppløsningsmiddel.
2. Fremgangsmåte ifølge krav 1,
karakterisert ved at det gassformige hydrogenklorid og det gassformige hydrogensulfid anvendes i form av en blanding.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8025275A FR2495157A1 (fr) | 1980-11-28 | 1980-11-28 | Procede nouveau de preparation des tetrahydro-5, 6, 7, 7a 4h-thieno (3, 2-c) pyridinones-2 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO814056L NO814056L (no) | 1982-06-01 |
| NO155666B true NO155666B (no) | 1987-01-26 |
| NO155666C NO155666C (no) | 1987-05-06 |
Family
ID=9248449
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO814056A NO155666C (no) | 1980-11-28 | 1981-11-27 | Fremgangsmaate for fremstilling av 5,6,7,7a-tetrahydro-4h-thieno-(3,2-c)-pyridin-2-on-derivater. |
Country Status (37)
| Country | Link |
|---|---|
| US (1) | US4424356A (no) |
| EP (1) | EP0053949B1 (no) |
| KR (1) | KR870000823B1 (no) |
| AR (1) | AR228166A1 (no) |
| AT (1) | ATE5725T1 (no) |
| AU (1) | AU543463B2 (no) |
| BG (1) | BG36347A3 (no) |
| CA (1) | CA1182116A (no) |
| CS (1) | CS224635B2 (no) |
| CY (1) | CY1280A (no) |
| DD (1) | DD201798A5 (no) |
| DE (1) | DE3161798D1 (no) |
| DK (1) | DK152131C (no) |
| EG (2) | EG15453A (no) |
| ES (1) | ES8207181A1 (no) |
| FI (1) | FI72726C (no) |
| FR (1) | FR2495157A1 (no) |
| GR (1) | GR78022B (no) |
| HK (1) | HK61585A (no) |
| HU (1) | HU185070B (no) |
| IE (1) | IE51710B1 (no) |
| IL (1) | IL64148A (no) |
| IN (1) | IN155555B (no) |
| MA (1) | MA19332A1 (no) |
| MY (1) | MY8600007A (no) |
| NO (1) | NO155666C (no) |
| NZ (1) | NZ199023A (no) |
| OA (1) | OA06952A (no) |
| PH (1) | PH19848A (no) |
| PL (1) | PL127918B1 (no) |
| PT (1) | PT73989B (no) |
| RO (1) | RO83468B (no) |
| SU (1) | SU1176843A3 (no) |
| TR (1) | TR21229A (no) |
| YU (1) | YU42595B (no) |
| ZA (1) | ZA817876B (no) |
| ZW (1) | ZW27281A1 (no) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2495156A1 (fr) * | 1980-11-28 | 1982-06-04 | Sanofi Sa | Derives de la thieno-pyridinone, leur procede de preparation et leur application therapeutique |
| FR2528848A1 (fr) * | 1982-06-16 | 1983-12-23 | Sanofi Sa | Nouveau derive de thieno-pyridone, son procede de preparation et son application therapeutique |
| FR2576901B1 (fr) * | 1985-01-31 | 1987-03-20 | Sanofi Sa | Nouveaux derives de l'acide a-(oxo-2 hexahydro-2,4,5,6,7,7a thieno (3,2-c) pyridyl-5) phenyl acetique, leur procede de preparation et leur application therapeutique |
| CA1337695C (en) * | 1988-09-23 | 1995-12-05 | Jacques Gosteli | Process for the production of 4,5,6,7-tetrahydrothieno-¬3,2-c|-pyridines |
| FR2652579B1 (fr) * | 1989-10-02 | 1992-01-24 | Sanofi Sa | Derives d'hydroxy-2 thiophene et furanne condenses avec un cycle azote, sur procede de preparation et leur application en therapeutique. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2215948B1 (no) * | 1973-02-01 | 1976-05-14 | Centre Etd Ind Pharma | |
| FR2338703A1 (fr) * | 1976-01-22 | 1977-08-19 | Parcor | Derives de thieno (3,2-c) pyridine, leur procede de preparation et leurs applications |
-
1980
- 1980-11-28 FR FR8025275A patent/FR2495157A1/fr active Granted
-
1981
- 1981-10-14 DE DE8181401595T patent/DE3161798D1/de not_active Expired
- 1981-10-14 EP EP81401595A patent/EP0053949B1/fr not_active Expired
- 1981-10-14 AT AT81401595T patent/ATE5725T1/de not_active IP Right Cessation
- 1981-10-14 CY CY1280A patent/CY1280A/xx unknown
- 1981-10-28 IL IL64148A patent/IL64148A/xx unknown
- 1981-10-30 DK DK480681A patent/DK152131C/da not_active IP Right Cessation
- 1981-11-02 FI FI813436A patent/FI72726C/fi not_active IP Right Cessation
- 1981-11-04 EG EG636/81A patent/EG15453A/xx active
- 1981-11-04 EG EG638/81A patent/EG16504A/xx active
- 1981-11-06 IN IN1237/CAL/81A patent/IN155555B/en unknown
- 1981-11-11 PH PH26484A patent/PH19848A/en unknown
- 1981-11-11 ZW ZW272/81A patent/ZW27281A1/xx unknown
- 1981-11-12 AU AU77431/81A patent/AU543463B2/en not_active Ceased
- 1981-11-13 PT PT73989A patent/PT73989B/pt unknown
- 1981-11-13 ZA ZA817876A patent/ZA817876B/xx unknown
- 1981-11-13 MA MA19536A patent/MA19332A1/fr unknown
- 1981-11-14 OA OA57548A patent/OA06952A/xx unknown
- 1981-11-16 ES ES507706A patent/ES8207181A1/es not_active Expired
- 1981-11-16 BG BG054163A patent/BG36347A3/xx unknown
- 1981-11-16 AR AR287458A patent/AR228166A1/es active
- 1981-11-17 GR GR66544A patent/GR78022B/el unknown
- 1981-11-17 IE IE2685/81A patent/IE51710B1/en unknown
- 1981-11-20 NZ NZ199023A patent/NZ199023A/en unknown
- 1981-11-24 TR TR21229A patent/TR21229A/xx unknown
- 1981-11-25 CS CS818684A patent/CS224635B2/cs unknown
- 1981-11-26 PL PL1981233981A patent/PL127918B1/pl unknown
- 1981-11-26 DD DD81235155A patent/DD201798A5/de unknown
- 1981-11-27 CA CA000391063A patent/CA1182116A/en not_active Expired
- 1981-11-27 YU YU2789/81A patent/YU42595B/xx unknown
- 1981-11-27 KR KR1019810004594A patent/KR870000823B1/ko active IP Right Grant
- 1981-11-27 HU HU813561A patent/HU185070B/hu not_active IP Right Cessation
- 1981-11-27 SU SU813358458A patent/SU1176843A3/ru active
- 1981-11-27 RO RO105884A patent/RO83468B/ro unknown
- 1981-11-27 NO NO814056A patent/NO155666C/no unknown
- 1981-11-30 US US06/325,795 patent/US4424356A/en not_active Expired - Fee Related
-
1985
- 1985-08-15 HK HK615/85A patent/HK61585A/xx unknown
-
1986
- 1986-12-30 MY MY7/86A patent/MY8600007A/xx unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2094428C1 (ru) | Способ получения бензопирановых соединений, промежуточные соединения и способы их получения | |
| SU683625A3 (ru) | Способ получени 4,5,6,7-тетрагидротиено-(2,3-с)-или-(3,2-с)-пиридинов или их солей | |
| NO155666B (no) | Fremgangsmaate for fremstilling av 5,6,7,7a-tetrahydro-4h-thieno-(3,2-c)-pyridin-2-on-derivater. | |
| US4414416A (en) | Certain diacetyl-amino-phenolic derivatives | |
| US5107057A (en) | Cyano-dienes, halopyridines, intermediates and a process for their preparation | |
| SU1301311A3 (ru) | Способ получени производных гексагидроазепина или пиперидина, или пирролидина (его варианты) | |
| US4965359A (en) | Process for the production of 4,5,6,7-tetrahydrothieno-[3,2-C]-pyridines | |
| CA1182117A (en) | Process for making 5,6,7,7a-tetrahydro-4h- thieno- [)3,2,-c]pyridin-2-one | |
| DK163180B (da) | P-nitrophenyl-3-brom-2,3-diethoxypropionat | |
| FI113859B (fi) | Uusia menetelmiä (S)-4-amino-hepta-5,6-dieenihapon ja sen välituotteiden valmistamiseksi sekä uudet välituotteet | |
| US5142091A (en) | α, β-unsaturated ketones and ketoxime derivatives | |
| US3196161A (en) | Process for preparing alkyl 3-alkyl-isoxazole-5-carboxylate | |
| Hahn et al. | Synthesis of new dihydrooxathiino [2, 3‐b] quinoline | |
| US4299968A (en) | Novel thiophene compounds | |
| US4656289A (en) | 1,3-dibenzyl-4-halohexahydro-1H-thieno[3,4-d]imidazol-2(3H)-one intermediates | |
| NO863769L (no) | Fremgangsmaate for fremstilling av 4-hydroksy-2-oksopyrrolin-1-yl-acetamid. | |
| Jilale et al. | Synthesis of cyclopentathiophenacetic acid derivatives. Reactivity of methyl 6‐oxo‐4, 5‐dihydro‐6H‐cyclopenta [b] thiophen‐4‐acetate | |
| US4360681A (en) | Novel thiophene compounds | |
| US4051150A (en) | 3-(2-Dialkylamino-2-dialkylphosphonylvinyl)-6,11-dihydrodibenzo-[b.e.]-thiepin-11-one | |
| SU549075A3 (ru) | Способ получени производных флуоренона или их солей | |
| SU383293A1 (ru) | СПОСОБ ПОЛУЧЕНИЯ КИСЛОТНЫХ СОЛЕЙ ИНДЕНОПИРИДИНОВ1Изобретение относитс к области получени новых кислотных солей инденопиридинов, об- ладаюидих высокой фитологической активностью.Известны инденопиридины и их кислотные соли общей формулы (I), содержащие в положении «5» заместитель и полученные реакцией дегидратации соответствующих 5-окси- соединений.-CH-CH-CCH^VR^ Кз Riсогде RI — водород, низший алкил, С1, Вг илиF; R2—CN, —COORs; —CON (^R. R»' | |
| US20040054197A1 (en) | Styrene derivatives and process for production thereof | |
| AU2946889A (en) | Cyano-dienes, halopyridines, intermediates and a process for their preparation | |
| NO313283B1 (no) | Fremgangsmåte for fremstilling av tetrahydropyridinderivat | |
| IT9020084A1 (it) | Processo per la preparazione di derivati di acidi 1, 2-diidro 3h pirrol (1, 2-a) pirrol-l-carbossilici e relativi intermedi |