NO762723L - HYDROLYTICAL PROCEDURE FOR THE PREPARATION OF 6,11-DIHYDRODIBENZO- (B.E.) - THIEPIN-11-ONE-3-ACETIC ACID - Google Patents
HYDROLYTICAL PROCEDURE FOR THE PREPARATION OF 6,11-DIHYDRODIBENZO- (B.E.) - THIEPIN-11-ONE-3-ACETIC ACIDInfo
- Publication number
- NO762723L NO762723L NO762723A NO762723A NO762723L NO 762723 L NO762723 L NO 762723L NO 762723 A NO762723 A NO 762723A NO 762723 A NO762723 A NO 762723A NO 762723 L NO762723 L NO 762723L
- Authority
- NO
- Norway
- Prior art keywords
- thiepin
- dihydrodibenzo
- solution
- acid
- acetic acid
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 4
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical group [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims 1
- 239000000243 solution Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 8
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- -1 alkali metal salts Chemical class 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 235000011114 ammonium hydroxide Nutrition 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 229910001961 silver nitrate Inorganic materials 0.000 description 4
- YMDCGVVDZQFCPH-UHFFFAOYSA-N 2-benzylsulfanylterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(SCC=2C=CC=CC=2)=C1 YMDCGVVDZQFCPH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 206010061218 Inflammation Diseases 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 239000000908 ammonium hydroxide Substances 0.000 description 3
- WGRYDTFDVJDMCG-UHFFFAOYSA-N dipropan-2-yl 2-nitrobenzene-1,4-dicarboxylate Chemical compound CC(C)OC(=O)C1=CC=C(C(=O)OC(C)C)C([N+]([O-])=O)=C1 WGRYDTFDVJDMCG-UHFFFAOYSA-N 0.000 description 3
- 230000004054 inflammatory process Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 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
- 150000007513 acids Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 210000003754 fetus Anatomy 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 2
- QUMITRDILMWWBC-UHFFFAOYSA-N nitroterephthalic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C([N+]([O-])=O)=C1 QUMITRDILMWWBC-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000035935 pregnancy Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000012312 sodium hydride Substances 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 208000010392 Bone Fractures Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005909 Kieselgur Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000006670 Multiple fractures Diseases 0.000 description 1
- ZRKWMRDKSOPRRS-UHFFFAOYSA-N N-Methyl-N-nitrosourea Chemical compound O=NN(C)C(N)=O ZRKWMRDKSOPRRS-UHFFFAOYSA-N 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 239000006286 aqueous extract Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 1
- OQNGCCWBHLEQFN-UHFFFAOYSA-N chloroform;hexane Chemical compound ClC(Cl)Cl.CCCCCC OQNGCCWBHLEQFN-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- SPWVRYZQLGQKGK-UHFFFAOYSA-N dichloromethane;hexane Chemical compound ClCCl.CCCCCC SPWVRYZQLGQKGK-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- HRXCTGGMTOEWFE-UHFFFAOYSA-N dipropan-2-yl 2-benzylsulfanylbenzene-1,4-dicarboxylate Chemical compound CC(C)OC(=O)C1=CC=C(C(=O)OC(C)C)C(SCC=2C=CC=CC=2)=C1 HRXCTGGMTOEWFE-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910003002 lithium salt Inorganic materials 0.000 description 1
- 159000000002 lithium salts Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 229940035363 muscle relaxants Drugs 0.000 description 1
- 210000002346 musculoskeletal system Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000000050 smooth muscle relaxant Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D337/00—Heterocyclic compounds containing rings of more than six members having one sulfur atom as the only ring hetero atom
- C07D337/02—Seven-membered rings
- C07D337/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D337/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D337/12—[b,e]-condensed
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Hydrolysemetode for fremstilling a* 6,11-dihydrodibenzo-(b.e)tiepin-ll-on-3-eddiksyre. ;Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av 6,11-dihydrodibenzo-(b.e)tiepin-ll-on-3-eddiksyre med formel ; ; og deres alkalimetallsalter (dvs. natrium-, kalium- og litium-salter) ved baéehydrolyse av forbindelsens amider. Disse forbindelser er egnet som antiinfl&mmatoriske, antipyretiske-og smertestillende midler, blodpropp-inhibitorer, fibrinolytiske midler og glattmuskelavslappende midler. De kan brukes både■ profylaktisk og terapeutisk. ;Derfor er preparater som inneholder disse forbindelser nyttige ved behandling av betennelser i det. muskulære skjelettsystem, ledd og andre vev, f.eks. ved behandling av betennelsestilstander som reumatisme, sjokk, opprivende sår, arthritis, benbrudd, post-traumatiske tilstander og giktfeber. ;I de tilfeller hvor ovenstående tilstander omfatter smerte og feber samt betennelse, vil de foreliggende forbindelser være egnet for opphevelse av disse, tilstander samt bet.ennelsen. ;Forbindelsen med formel A og deres salter er også muskelavslappende på de glatte muskler i livmoren og er derfor . egnet for å opprettholde svangerskapet hos gravide pattedyr til beste for både mor og/eller .foster inntil graviditetsperioden er avsluttet fra et medisinsk synspunkt eller er mer gunstig for moren eller fosteret. ;Den foreliggende fremgangsmåte kan illustreres ved følgende reaksjonsskjerna: ; hvor R betegner hydrogen eller en lavere alkylgruppe med 1-4 karbonatomer. ;Ved utførelse av ovenstående fremgangsmåte behandles et utgangsstoff med formel I, dvs. 3-diazoacetyl-6,11-dihydro-dibenzo-(b.e.)tiepin-ll-on med en vandig oppløsning av ammoniumhydroksyd eller lavere alkylprimæramin i nærvær av sølvnitrat i et egnet vann-"blandbart organisk inert oppløsningsmiddel med høyt kokepunkt for fremstilling av det tilsvarende ammo- eller substituert amino-derivat med formel (II). ;Reaksjonen utføres ved 90-120°C i løpet av fra 20 min. til 4 timer. ;Mengden reagenser er ikke avgjørende, det foretrek-kes imidlertid generelt å bruke 3-10 molekvivalenter av både ammoniumhydroksyd (eller amin) og sølvnitrat. ;Eksempler på egnede primære aminer er metylamin, etylamin, isopropylamin, n-butylamin, etc. Egnede organiske oppløsningsmidler som er blandbare med vann er slike med kokepunkt innenfor eller høyere enn ovenstående område, f..eks. dioksan, diglym, triglym og lignende. ;Ved en foretrukket utførelse utføres reaksjonen i vandig dioksan ved tilbakeløpstemperatur i ca. 30 min. når man bruker ammoniumhydroksyd og i 2-4 timer når man bruker et amin. ;Basehydrolyse av et amid med formel II gir det ønskede 6,11-dihydrodibenzo-(b.e)tiepin-ll-on-3-eddiksyre (A) via'et salt av denne. Hydrolysen skjer ved en sterk base, f.eks. et alkalimetallhydroksyd som natriumhydroksyd, kalium- ;v ;hydroksyd, eller litiumhydroksyd i vandig høytkokende inert ;. oppløsningsmiddel som etylenglykol eller propylenglykol.og ved en temperatur på 120-220°C, fortrinnsvis ved. tilbakeløpskoking, over en '.periode som kan variere fra 30 min. til 5 timer. Reaksjonen gir saltet av den basen som brukes og dette kan lett overføres til den frie syre ved behandling med en kraftig syre som f.eks. saltsyre, svovelsyre, fosforsyre og lignende. ;Utgangsstoffet med formel I kan fremstilles som beskrevet f.eks. i den parallelle US-søknad nr. 634.086/75 - f ra samme søker. ;I korthet består metoden i forestring avnitro-tereftalsyre med isopropanol i nærvær av en syrekatalysator under dannelse av diisopropylnitrotereftalat fulgt av behandling med benzylmerkaptan og natriumhydrid i et egnet organisk opp-løsningsmiddel for fremstilling av •iiisopropyl(benzyltio)-tereftalat som ved alkalisk hydrolyse gir (benzyltio)-teref tal-syre. • ;Sistnevnte forbindelse behandles med tionylklorid og det dannede (benzyltio)-tereftalylklorid ringsluttes igjen til 6 ,11-dihydrodi-benzo-(b . e . ) tiepin-ll-on-3-karbonylklorid ved behandling med nitrometan og alum^iiumklorid i egnet organisk oppløsningsmiddel. Omsetning av denne forbindelse med eterisk diazometan gir det ønskede 3~diazoacetyl-6,11-dihydrodibenzo-(b.e. )tiepin-ll-on (I). ;De nedenstående eksempler skal illustrere foretrukne utførelser av oppfinnelsen men skal ikke begrense dens ramme. Produktutbytter kan variere avhengig av reagenser, betingelser og opparbeidelse. Generelt ligger imidlertid utbyttene i området 30-60 %. ;Prosess 1 ;En oppløsning av 200 g nitrotereftalsyre i 1 liter isopropanol mettes med hydrogenklorid og kokes med tilbakeløp i 3 dager. (I løpet av dette tidsrom tilsettes det med mellomrom ;hydrogenklorid til oppløsningen for å holde konsentrasjonen). Reaksjonsoppløsningen blir deretter avkjølt og isopropanolen ;• inndampet under nedsatt trykk, hvilket gir en rest som oppløses i 500 ml metylenklorid. Den dannede oppløsning vaskes med 10 % ;vandig natriumkarbonat og det organiske sjikt tørkes over magnesiumsulfat hvorpå man fjerner oppløsningsmidlet under ned- ;v ;satt trykk, .hvilket gir 2^5 g (utbytte 87,5..%) diisopropylnitrotereftalat, som en olje<*>I.R.: v^jb172<4,>1542, 1350 cm"<1.>N.M.R. «TMS<3>"3lj35(6H'd)'1>i|0(6H>d)'5>2k (1H'7 linJer)> 5,27 (1HV 7 linjer), 7,71 (1H, d), 8,24 (lH,.dd), 8,43 ppm (1H, d). Hydrolysis method for the preparation of a* 6,11-dihydrodibenzo-(b.e)thiepin-11-one-3-acetic acid. The present invention relates to a process for the production of 6,11-dihydrodibenzo-(b.e)thiepin-11-one-3-acetic acid with the formula; ; and their alkali metal salts (ie sodium, potassium and lithium salts) by baée hydrolysis of the amides of the compound. These compounds are suitable as anti-inflammatory, antipyretic and analgesic agents, blood clot inhibitors, fibrinolytic agents and smooth muscle relaxants. They can be used both ■ prophylactically and therapeutically. Therefore, preparations containing these compounds are useful in the treatment of inflammation in it. musculoskeletal system, joints and other tissues, e.g. in the treatment of inflammatory conditions such as rheumatism, shock, excruciating wounds, arthritis, broken bones, post-traumatic conditions and gouty fever. In those cases where the above conditions include pain and fever as well as inflammation, the present compounds will be suitable for eliminating these conditions and the inflammation. The compound with formula A and their salts are also muscle relaxants on the smooth muscles of the uterus and are therefore . suitable for maintaining pregnancy in pregnant mammals for the benefit of both mother and/or fetus until the period of pregnancy is terminated from a medical point of view or is more beneficial to the mother or fetus. ;The present method can be illustrated by the following reaction core: ; where R denotes hydrogen or a lower alkyl group with 1-4 carbon atoms. In carrying out the above process, a starting material of formula I, i.e. 3-diazoacetyl-6,11-dihydro-dibenzo-(b.e.)thiepin-11-one is treated with an aqueous solution of ammonium hydroxide or lower alkyl primary amine in the presence of silver nitrate in a suitable water-miscible organic inert solvent with a high boiling point for the preparation of the corresponding amino or substituted amino derivative of formula (II). The reaction is carried out at 90-120°C during from 20 min. to 4 hours. ; The amount of reagents is not critical, however, it is generally preferred to use 3-10 molar equivalents of both ammonium hydroxide (or amine) and silver nitrate. Examples of suitable primary amines are methylamine, ethylamine, isopropylamine, n-butylamine, etc. Suitable organic solvents which are miscible with water are those with a boiling point within or higher than the above range, e.g. dioxane, diglyme, triglyme and the like. In a preferred embodiment, the reaction is carried out in aqueous dioxane at reflux temperature for about. 30 min. when using ammonium hydroxide and for 2-4 hours when using an amine. Base hydrolysis of an amide of formula II gives the desired 6,11-dihydrodibenzo-(b.e)thiepin-11-one-3-acetic acid (A) via its salt. The hydrolysis takes place with a strong base, e.g. an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide in aqueous high-boiling inert ;. solvent such as ethylene glycol or propylene glycol.and at a temperature of 120-220°C, preferably at. reflux, over a period which can vary from 30 min. to 5 hours. The reaction gives the salt of the base used and this can easily be transferred to the free acid by treatment with a strong acid such as hydrochloric acid, sulfuric acid, phosphoric acid and the like. The starting material with formula I can be prepared as described, e.g. in the parallel US application no. 634,086/75 - from the same applicant. Briefly, the method consists in the esterification of nitroterephthalic acid with isopropanol in the presence of an acid catalyst to form diisopropylnitroterephthalate, followed by treatment with benzylmercaptan and sodium hydride in a suitable organic solvent for the production of iiisopropyl(benzylthio)terephthalate, which on alkaline hydrolysis gives (benzylthio)-terephthalic acid. • ;The latter compound is treated with thionyl chloride and the formed (benzylthio)-terephthalyl chloride is ring-closed again to 6,11-dihydrodi-benzo-(b . e . ) thiepine-ll-one-3-carbonyl chloride by treatment with nitromethane and aluminum chloride in suitable organic solvent. Reaction of this compound with ethereal diazomethane gives the desired 3-diazoacetyl-6,11-dihydrodibenzo-(b.e. )thiepin-ll-one (I). The following examples shall illustrate preferred embodiments of the invention but shall not limit its scope. Product yields may vary depending on reagents, conditions and work-up. In general, however, yields are in the range of 30-60%. ;Process 1 ;A solution of 200 g of nitroterephthalic acid in 1 liter of isopropanol is saturated with hydrogen chloride and refluxed for 3 days. (During this period, hydrogen chloride is added to the solution at intervals to maintain the concentration). The reaction solution is then cooled and the isopropanol is evaporated under reduced pressure, which gives a residue which is dissolved in 500 ml of methylene chloride. The resulting solution is washed with 10% aqueous sodium carbonate and the organic layer is dried over magnesium sulfate, after which the solvent is removed under reduced pressure, which gives 2^5 g (yield 87.5%) of diisopropyl nitroterephthalate, as a oil<*>I.R.: v^jb172<4,>1542, 1350 cm"<1.>N.M.R. «TMS<3>"3lj35(6H'd)'1>i|0(6H>d)'5>2k (1H'7 lines) > 5.27 (1HV 7 lines), 7.71 (1H, d), 8.24 (1H,.dd), 8.43 ppm (1H, d).
B. Til en avkjølt (-20°C) oppløsning av 23,5 ml benzylmerkaptan i 100 ml dimetylformamid setter man langsomt 5,1 g natriumhydrid. Den dannede oppløsning avkjøles til -30°C .og man tilsetter 53 g diisopropylnitrotereftalat i 100 ml dimetylformamid. Etter en time ved -30°C og 2 timer ved 0°C helles reaksjonsblandingen ut i vann, fellingen filtreres fra, vaskes med vann og tørkes og gir 77-92 % rå diisopropyl-(benzyltio)-tereftalat som ved omkrystallisasjon fra pentan smelter ved 70-7.1°C. C. Den rå diisopropyl-(berJÉyltio)-tereftalat som er fremstilt under del B kokes ved tilbakeløp med 500 ml metanol, 25 g kaliumhydroksyd og 50 ml vann i 2 timer. Reaksjonsblandingen blir derpå konsentrert til et lite volum, avkjølt, fortynnet med vann og filtrert gjennom diatomejord (celitt). Filtratet surgjøres med 4N saltsyre og den dannede felling filtreres fra og tørkes i ovn ved 90-100°C og gi? 45 g (87 %) (benzyltio)-'tereftalsyre med smp. 299-300°C. B. To a cooled (-20°C) solution of 23.5 ml of benzyl mercaptan in 100 ml of dimethylformamide, slowly add 5.1 g of sodium hydride. The resulting solution is cooled to -30°C and 53 g of diisopropyl nitroterephthalate in 100 ml of dimethylformamide are added. After one hour at -30°C and 2 hours at 0°C, the reaction mixture is poured into water, the precipitate is filtered off, washed with water and dried to give 77-92% crude diisopropyl-(benzylthio)-terephthalate which melts on recrystallization from pentane at 70-7.1°C. C. The crude diisopropyl-(berylthio)terephthalate prepared under part B is refluxed with 500 ml of methanol, 25 g of potassium hydroxide and 50 ml of water for 2 hours. The reaction mixture is then concentrated to a small volume, cooled, diluted with water and filtered through diatomaceous earth (celite). The filtrate is acidified with 4N hydrochloric acid and the formed precipitate is filtered off and dried in an oven at 90-100°C and give? 45 g (87%) of (benzylthio)-terephthalic acid with m.p. 299-300°C.
D. En blanding av 10 g (benzyltio)-tereftalsyre og 10 ml tionylklorid kokes ved tilbakeløp i 4 timer. "Etter å ha fjernet overskudd av tionylklorid i vakuum oppslemmes inndampningsresten med heksan og det faste stoff filtreres fra og gir. 10,2 g (92 %) D. A mixture of 10 g of (benzylthio)terephthalic acid and 10 ml of thionyl chloride is refluxed for 4 hours. "After removing excess thionyl chloride in vacuo, the evaporation residue is slurried with hexane and the solid is filtered off to give 10.2 g (92%)
(benzyltio)-tereftalylklorid med smp. 158°C. (benzylthio)-terephthalyl chloride with m.p. 158°C.
E. En oppløsning av 10,2 g (benzyltio)-tereftalylklorid i 100 ml metylenklorid settes til en oppløsning av 14,75 g aluminiumklorid i 100 ml metylenklorid som inneholder 10,51 nil nitrometan. Etter 5 timer ved 25°C tilsettes 16,5 ml mettet vandig natriumklorid under kraftig røring. De uorganiske salter som utfelles.filtreres fra og filtratet avdampes til en fast rest som oppslemmes med eter. Eteroppslemmingen filtreres og gir 7,0 g (70,7 %) 6,ll-dihydrodibenzo(b.e.)tiepin-ll-on-3-karbonyl-klorid med smp. 119-120°C. E. A solution of 10.2 g of (benzylthio)-terephthalyl chloride in 100 ml of methylene chloride is added to a solution of 14.75 g of aluminum chloride in 100 ml of methylene chloride containing 10.51 nil of nitromethane. After 5 hours at 25°C, 16.5 ml of saturated aqueous sodium chloride are added with vigorous stirring. The inorganic salts that precipitate are filtered off and the filtrate is evaporated to a solid residue which is slurried with ether. The ether slurry is filtered to give 7.0 g (70.7%) of 6,11-dihydrodibenzo(b.e.)thiepin-11-one-3-carbonyl chloride of m.p. 119-120°C.
F. En oppløsning av 11 g 6,11-dihydrodibenzo(b.e.)- tiepin-ll-on-3-k-arbonylklorid i 100 ml metylenklorid settes langsomt til et overskudd av diazometan (fremstilt fra 20 g N-nitroso-N-metylurea) i 200 ml eteroppløsnlng. Etter 2 timer konsentreres reaksjonsblandingen til ca. 50 ml ved å koke bort oppløsningsmidlet og blandingen avkjøles. Den avkjølte reak-sjonsblanding filtreres og gir en rest på 9,5 g (85 %) 3_diazo-acetyl-6,11-dihydrodibenzo(b.e.)-tiepin-ll-on med smp. på 153°C (dekomp.). F. A solution of 11 g of 6,11-dihydrodibenzo(b.e.)-thiepin-1-one-3-k-carbonyl chloride in 100 ml of methylene chloride is added slowly to an excess of diazomethane (prepared from 20 g of N-nitroso-N-methylurea ) in 200 ml ether solution. After 2 hours, the reaction mixture is concentrated to approx. 50 ml by boiling off the solvent and the mixture is cooled. The cooled reaction mixture is filtered and gives a residue of 9.5 g (85%) of 3-diazo-acetyl-6,11-dihydrodibenzo(b.e.)-thiepin-11-one with m.p. at 153°C (decomp.).
Eksempel 1 Example 1
A. En-oppløsning av 500 mg 3-diazoacetyl-6,11-dihydro-dibenzo- (b.e.)tiepin-ll-on i 20 ml destillert dioksan behandles med 7 ml vandig ammoniakkoppløsning (sp.v. 0,880) og 5 ml 10 % vandig sølvnitratoppløsning. Reaksjonsblandingen kokes ved tilbakeløp i 30 min., avkjøles, fortynnes med 30 ml mettet natriumkloridoppløsning og ekstraheres med etylacetat (2 x 50 ml). De samlede ekstrakter vaskes ^.ed mettet natriumkloridopp-løsning, tørkes på, vannfri natriumsulfat og inndampes til tørr-het under nedsatt trykk, som gir et fast stoff som ved omkryst-allisering fra metylenklorid-heksan gir'380 mg 3_acetamido-6,11-dihydrodibenzo ( b . e .) tiepin-ll-on (II, R=H), med smp. l62°C. A. A solution of 500 mg of 3-diazoacetyl-6,11-dihydro-dibenzo-(b.e.)thiepin-ll-one in 20 ml of distilled dioxane is treated with 7 ml of aqueous ammonia solution (p.v. 0.880) and 5 ml of 10 % aqueous silver nitrate solution. The reaction mixture is refluxed for 30 min., cooled, diluted with 30 ml of saturated sodium chloride solution and extracted with ethyl acetate (2 x 50 ml). The combined extracts are washed with saturated sodium chloride solution, dried on anhydrous sodium sulfate and evaporated to dryness under reduced pressure, which gives a solid which, on recrystallization from methylene chloride-hexane, gives 380 mg of 3-acetamido-6,11 -dihydrodibenzo ( b . e .) thiepin-ll-one (II, R=H), with m.p. 162°C.
B. En_. oppløsning av 170 mg 3-acetamido-6 ,11-dihydrodi-benzo- (b.e.)tiepin-ll-on i 10 ml egylenglykol behandles med én oppløsning av 50 mg kaliumhydroksyd i 10 ml vann. Reaksjonsblandingen kokes ved tilbakeløp i 1 time, avkjøles, surgjøres med 10 %ig vandig saltsyre, fortynnes med 50 ml vann og ekstraheres med etylacetat (2 x 50 ml). De samlede ekstrakter vaskes med vann og ekstraheres med 10 ml 10 %ig vandig kaliumkarbonat. Surgj øring av det basiske vandige ekstrakt med' 10 % saltsyre gir en felling som filtreres fra og lufttørkes. På denne måten får man 117 mg 6,11-dihydrodibenzo-(b.e.)tiepin-ll-on-3-eddiksyre B. One_. solution of 170 mg of 3-acetamido-6,11-dihydrodi-benzo-(b.e.)thiepin-11-one in 10 ml of ethylene glycol is treated with one solution of 50 mg of potassium hydroxide in 10 ml of water. The reaction mixture is refluxed for 1 hour, cooled, acidified with 10% aqueous hydrochloric acid, diluted with 50 ml of water and extracted with ethyl acetate (2 x 50 ml). The combined extracts are washed with water and extracted with 10 ml of 10% aqueous potassium carbonate. Acidification of the basic aqueous extract with 10% hydrochloric acid gives a precipitate which is filtered off and air-dried. In this way, 117 mg of 6,11-dihydrodibenzo-(b.e.)thiepin-1-one-3-acetic acid is obtained
(A) med smp. 152-153°C, identisk med en autentisk prøve. (A) with m.p. 152-153°C, identical to an authentic sample.
På lignende måte kan andre sterke baser som natriumhydroksyd og andre sterke syrer som svovelsyre brukes under trinn B ovenfor. Similarly, other strong bases such as sodium hydroxide and other strong acids such as sulfuric acid can be used during step B above.
Eksempel 2 Example 2
En oppløsning av 200 mg 3-diazoacetyl-6,11-dihydro-dibenzo- ( b . e .) tiepin-ll-on i 8 ml destillert dioksan behandles med 5,6 ml 40 #ig vandig metylaminoppløsning og 2,0 ml 10 #ig vandig sølvnitratoppløsning. Reaksjonsblandingen kokes, ved tilbakeløp i 3 timer, avkjøles, fortynnes m,ed vann og ekstraheres med etylacetat. De samlede ekstrakter"vaskes, med mettet natriumkloridoppløsning, tørkes på vannfri natriumsulfat og 'inndampes til tørrhet.under nedsatt trykk. Oljeresten kromato-graferes'■på 5,0 g silisiumdioksydgel, elueres med kloroform. Inndampning av eluatet og krystallisering av resten fra kloroform-heksan gir 130 mg N-metyl-6 ,11-dihydrodibenzo-(b . e ..) - tiepin-ll-on-3-acetamid (II, R = Me), med smp. l63-l65°C. A solution of 200 mg of 3-diazoacetyl-6,11-dihydro-dibenzo-( b . e .) tiepin-ll-one in 8 ml of distilled dioxane is treated with 5.6 ml of 40 #ig aqueous methylamine solution and 2.0 ml of 10 #ig aqueous silver nitrate solution. The reaction mixture is boiled at reflux for 3 hours, cooled, diluted with water and extracted with ethyl acetate. The combined extracts are washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The oil residue is chromatographed on 5.0 g of silica gel, eluted with chloroform. Evaporation of the eluate and crystallization of the residue from chloroform -hexane gives 130 mg of N-methyl-6,11-dihydrodibenzo-(b.e..)-thiepin-11-one-3-acetamide (II, R = Me), with mp 163-165°C.
B. En oppløsning av 50 mg N-metyl-6,11-dihydrodibenzo-(b. e. )tiepin-ll-on-3-acetamid i 3 nil etylenglykol kokes ved tilbakeløp i 1 time med 140 mg kaliumhydroksyd i 3 nil vann. Reaksjonsblandingen avkjøles, fortynnes med mettet natrium-kloridoppløsning, surgjøres med fortynnet vandig saltsyre og ekstraheres med etylacetat (2 x 25 ml). De samlede ekstrakter vaskes med vann og ekstraheres med 10 % vandig kaliumkarbonat-oppløsning. Det vandige basiske ekstrakt surgjøres med fortynnet saltsyre og fellingen filtreres fra, lufttørkes'og krystal-liseres fra metanol-vann til 28 mg 6,11-dihydrodibenzo-(b.e.)-tiepin-ll-on-3-eddiksyre (A) med smp. 152-153°C, identisk med en autentisk prøve. B. A solution of 50 mg of N-methyl-6,11-dihydrodibenzo-(b.e.)thiepin-11-one-3-acetamide in 3 nil of ethylene glycol is refluxed for 1 hour with 140 mg of potassium hydroxide in 3 nil of water. The reaction mixture is cooled, diluted with saturated sodium chloride solution, acidified with dilute aqueous hydrochloric acid and extracted with ethyl acetate (2 x 25 ml). The combined extracts are washed with water and extracted with 10% aqueous potassium carbonate solution. The aqueous basic extract is acidified with dilute hydrochloric acid and the precipitate is filtered off, air-dried and crystallized from methanol-water to give 28 mg of 6,11-dihydrodibenzo-(b.e.)-thiepin-11-one-3-acetic acid (A) with m.p. . 152-153°C, identical to an authentic sample.
Man kan benytte etylam 9in eller isopropylamin i stedet for metylamin under del Ai dette eksempel, hvilket gir lignende utbytter av 6,11-dihydrodibenzo-(b.e.)tiepin-ll-on-3-eddiksyre. One can use ethylamine 9in or isopropylamine instead of methylamine in part Ai of this example, giving similar yields of 6,11-dihydrodibenzo-(b.e.)thiepin-11-one-3-acetic acid.
På lignende måte kan man benytte andre sterke baser som kaliumhydroksyd og andre sterke syrer som svovelsyre og fosforsyre under trinn B ovenfor. In a similar way, you can use other strong bases such as potassium hydroxide and other strong acids such as sulfuric acid and phosphoric acid under step B above.
Claims (5)
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US69764976A | 1976-06-18 | 1976-06-18 |
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NO762723A NO762723L (en) | 1976-06-18 | 1976-08-05 | HYDROLYTICAL PROCEDURE FOR THE PREPARATION OF 6,11-DIHYDRODIBENZO- (B.E.) - THIEPIN-11-ONE-3-ACETIC ACID |
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DK (1) | DK351176A (en) |
ES (1) | ES459897A1 (en) |
FI (1) | FI762235A (en) |
NO (1) | NO762723L (en) |
SE (1) | SE7608719L (en) |
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1976
- 1976-08-03 SE SE7608719A patent/SE7608719L/en unknown
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- 1976-08-04 DK DK351176A patent/DK351176A/en unknown
- 1976-08-05 NO NO762723A patent/NO762723L/en unknown
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1977
- 1977-06-17 ES ES459897A patent/ES459897A1/en not_active Expired
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FI762235A (en) | 1977-12-19 |
DK351176A (en) | 1977-12-19 |
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