DK154081B - 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dion-forbindelser - Google Patents
2,3,4,5-tetrahydro-1-benzoxepin-3,5-dion-forbindelser Download PDFInfo
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- DK154081B DK154081B DK086188A DK86188A DK154081B DK 154081 B DK154081 B DK 154081B DK 086188 A DK086188 A DK 086188A DK 86188 A DK86188 A DK 86188A DK 154081 B DK154081 B DK 154081B
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- Denmark
- Prior art keywords
- tetrahydro
- benzoxepine
- dione
- benzoxepin
- compounds
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- VXHBBPNYWKGNHL-UHFFFAOYSA-N 1-benzoxepine-3,5-dione Chemical class O=C1CC(=O)COC2=CC=CC=C21 VXHBBPNYWKGNHL-UHFFFAOYSA-N 0.000 title description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 150000001875 compounds Chemical class 0.000 description 15
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 229910021529 ammonia Inorganic materials 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 239000012442 inert solvent Substances 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- BZCKRPHEZOHHBK-UHFFFAOYSA-N methyl 2-phenoxyacetate Chemical compound COC(=O)COC1=CC=CC=C1 BZCKRPHEZOHHBK-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- -1 alkali metal salts Chemical class 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 150000004820 halides Chemical class 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- QEPPAFNHWQMPAO-UHFFFAOYSA-N 3-amino-2h-1-benzoxepin-5-one Chemical class O1CC(N)=CC(=O)C2=CC=CC=C21 QEPPAFNHWQMPAO-UHFFFAOYSA-N 0.000 description 2
- WFLXHPHALXRMCM-UHFFFAOYSA-N 7-bromo-1-benzoxepine-3,5-dione Chemical compound O1CC(=O)CC(=O)C2=CC(Br)=CC=C21 WFLXHPHALXRMCM-UHFFFAOYSA-N 0.000 description 2
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229960005235 piperonyl butoxide Drugs 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SDTMFDGELKWGFT-UHFFFAOYSA-N 2-methylpropan-2-olate Chemical compound CC(C)(C)[O-] SDTMFDGELKWGFT-UHFFFAOYSA-N 0.000 description 1
- KJPSYRAPSMSKJT-UHFFFAOYSA-N 3-(methylamino)-7-nitro-2h-1-benzoxepin-5-one Chemical compound O1CC(NC)=CC(=O)C2=CC([N+]([O-])=O)=CC=C21 KJPSYRAPSMSKJT-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- GASXSJYBQJOITL-UHFFFAOYSA-N 7-bromo-3-(methylamino)-2h-1-benzoxepin-5-one Chemical compound O1CC(NC)=CC(=O)C2=CC(Br)=CC=C21 GASXSJYBQJOITL-UHFFFAOYSA-N 0.000 description 1
- KVHOLPABHNBTMQ-UHFFFAOYSA-N 7-bromo-8-methyl-1-benzoxepine-3,5-dione Chemical compound O1CC(=O)CC(=O)C2=C1C=C(C)C(Br)=C2 KVHOLPABHNBTMQ-UHFFFAOYSA-N 0.000 description 1
- ZMDKHKWFATYSAM-UHFFFAOYSA-N 7-chloro-1-benzoxepine-3,5-dione Chemical compound O1CC(=O)CC(=O)C2=CC(Cl)=CC=C21 ZMDKHKWFATYSAM-UHFFFAOYSA-N 0.000 description 1
- DAJQGGKRPPXIHB-UHFFFAOYSA-N 7-chloro-3-(methylamino)-2h-1-benzoxepin-5-one Chemical compound O1CC(NC)=CC(=O)C2=CC(Cl)=CC=C21 DAJQGGKRPPXIHB-UHFFFAOYSA-N 0.000 description 1
- MINMVFJKOGKNIZ-UHFFFAOYSA-N 7-chloro-8-methyl-1-benzoxepine-3,5-dione Chemical compound O1CC(=O)CC(=O)C2=C1C=C(C)C(Cl)=C2 MINMVFJKOGKNIZ-UHFFFAOYSA-N 0.000 description 1
- LVIYNTOWJVUGAN-UHFFFAOYSA-N 7-chloro-8-methyl-3-(methylamino)-2h-1-benzoxepin-5-one Chemical compound O1CC(NC)=CC(=O)C2=CC(Cl)=C(C)C=C21 LVIYNTOWJVUGAN-UHFFFAOYSA-N 0.000 description 1
- OEEIUZPPZJIYMC-UHFFFAOYSA-N 7-ethyl-3-(methylamino)-2h-1-benzoxepin-5-one Chemical compound O1CC(NC)=CC(=O)C2=CC(CC)=CC=C21 OEEIUZPPZJIYMC-UHFFFAOYSA-N 0.000 description 1
- DDSGUSAPKWQTRX-UHFFFAOYSA-N 7-fluoro-1-benzoxepine-3,5-dione Chemical compound O1CC(=O)CC(=O)C2=CC(F)=CC=C21 DDSGUSAPKWQTRX-UHFFFAOYSA-N 0.000 description 1
- WLYNTXJYZKDJHE-UHFFFAOYSA-N 7-methyl-1-benzoxepine-3,5-dione Chemical compound O1CC(=O)CC(=O)C2=CC(C)=CC=C21 WLYNTXJYZKDJHE-UHFFFAOYSA-N 0.000 description 1
- MLCGQYYNYSXDFI-UHFFFAOYSA-N 7-methyl-3-(methylamino)-2h-1-benzoxepin-5-one Chemical compound O1CC(NC)=CC(=O)C2=CC(C)=CC=C21 MLCGQYYNYSXDFI-UHFFFAOYSA-N 0.000 description 1
- NVVMPPAKGDTZAN-UHFFFAOYSA-N 8-chloro-3-(dimethylamino)-2h-1-benzoxepin-5-one Chemical compound O1CC(N(C)C)=CC(=O)C2=CC=C(Cl)C=C21 NVVMPPAKGDTZAN-UHFFFAOYSA-N 0.000 description 1
- AHKLHGCBLGLJNX-UHFFFAOYSA-N 8-chloro-3-(methylamino)-2h-1-benzoxepin-5-one Chemical compound O1CC(NC)=CC(=O)C2=CC=C(Cl)C=C21 AHKLHGCBLGLJNX-UHFFFAOYSA-N 0.000 description 1
- QRGGMYSKLSKBEP-UHFFFAOYSA-N 8-methyl-3-(methylamino)-2h-1-benzoxepin-5-one Chemical compound O1CC(NC)=CC(=O)C2=CC=C(C)C=C21 QRGGMYSKLSKBEP-UHFFFAOYSA-N 0.000 description 1
- PHYMIRJJHZIWRN-UHFFFAOYSA-N OC1=C(C=O)C(=O)COC2=CC=CC=C12 Chemical compound OC1=C(C=O)C(=O)COC2=CC=CC=C12 PHYMIRJJHZIWRN-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 150000004777 chromones Chemical class 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- LOQAFJZFPBWFKV-UHFFFAOYSA-N ethyl 2-(2-acetyl-4-bromo-5-methylphenoxy)acetate Chemical compound C(C)(=O)C1=C(OCC(=O)OCC)C=C(C(=C1)Br)C LOQAFJZFPBWFKV-UHFFFAOYSA-N 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910001392 phosphorus oxide Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical 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)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nutrition Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Epoxy Compounds (AREA)
Description
i
DK 154081 B
Opfindelsen angår hidtil ukendte 2,3,4,5-tetrahydro-l-benzoxepin-3,5-dionderivater, som er ejendommelige ved/ at de har den i kravet angivne formel Ila.
5 Por substituenterne 113' og R41 i formel Ila kommer som halogenatomer fluor, chlor, brom eller iod, især fluor, chlor eller brom, på tale. Alkylgrupperne med 1-4 car-bonatomer kan være ligekædede eller forgrenede, og især ved disubstitution på phenylgruppen er methyl fremher-10 skende. For nitro- eller trifluormethylgruppen er der alene tale om monosubstitution.
Det usubstituerede 2,3,4,5-tetrahydro-l-benzoxepin-3,5-dion er kendt fra en undersøgelse af omlejringsreak-15 tioner på chromoner, hvorved det blev opnået som hydrolyseprodukt af 2,3-dihydro-5-hydroxy-3-oxo-l-benzoxepin- 4-carbaldehyd (Synthesis (1977), side 61-63). Endvidere er 7-brom-8-methyl-2,3,4,5-tetrahydro-l-benzoxepin-3,5-dion blevet fundet i ringe mængde som biprodukt ved 20 ringslutningen af 2-acetyl-4-brom-5-methylphenoxyeddike-syre-ethylester til benzofuran-forbindelser (Tyman et al., Tetrahedron Letters 41 (1966),4993-4996).
Det har vist sig, at 2,3,4,5-tetrahydro-l-benzoxepin-25 3,5-dion-forbindelserne med formlen Ila ifølge opfindelsen udgør værdifulde mellemprodukter til fremstilling af tilsvarende 3-amino-l-benzoxepin-5(2H)-on-forbindel-ser, som har en god virkning på mavens motilitet.
30 Disse hidtil ukendte 3-amino-l-benzoxepin-5(2H)-on- forbindelser, deres farmakologiske egenskaber og deres fremstilling ud fra de her omhandlede 2,3,4,5-tetra-hydro-l-benzoxepin-3,5-dion-forbindelser er beskrevet i dansk patentansøgning nr. 3332/80.
35
DK 154081 B
2 2,3,4,5-tetrahydro-l-benzoxepin-3,5-dion-forbindelserne med formlen Ila ifølge opfindelsen kan fremstilles i godt udbytte ved omsætning af forbindelser med formlen 5
Sol·· - 10 4 xo-ch2-coor8 hvori R3' og R4' har den ovenstående betydning, og Rg 15 betyder en ligekædet eller forgrenet lavere alkylgruppe, fortrinsvis methyl, med en stærk base fra rækken lithi-umhydrid, natriumhydrid eller lithium-tert.-butoxid i nærvær af et inert opløsningsmiddel ved en temperatur mellem -70 °C og opløsningsmidlets kogetemperatur.
20
Som opløsningsmiddel egner sig især dimethylformamid eller tetrahydrofuran.
Til oparbejdning kan reaktionsblandingen tilsættes is-25 vand, og den udfældede forbindelse med formlen Ila skilles fra. Man kan imidlertid også adskille forbindelserne med formlen Ila fra biprodukterne ved udfældning af alkalimetalsaltene, især lithiumsaltet, med et upolært opløsningsmiddel, f.eks. toluen eller petroleumsether. Af 30 saltene kan den frie forbindelse så frigøres ved hjælp af en uorganisk eller organisk syre, f.eks. en vandig opløsning af saltsyre, svovlsyre eller eddikesyre.
Denne særlige fremgangsmåde er genstand for dansk 35 3
DK 154081 B
patentansøgning nr. 5178/85.
Forbindelserne med formlen Ila kan omdannes til 3-amino-l-benzoxepin-5(2H)-on-forbindelserne med den almene for-5 mel " 15 hvori Ri og R2 hver for sig betyder hydrogen, alkyl med 1-5 carbonatomer, som eventuelt er substitueret i ω-20 stillingen med en phenylgruppe eller alkyl med 2-5 carbonatomer, som er substitueret i ω-stillingen med en me-thoxygruppe, eller Ri og R2 sammen med nitrogenatomet hvortil de er knyttet, danner en mættet 5- til 7-leddet ring, som eventuelt indeholder et yderligere heteroatom 25 valgt blandt O og N, hvor det yderligere N-atom er substitueret med benzyl, og R3' og r4' hver for sig betyder halogen eller alkyl med 1-4 carbonatomer, eller en af R3' og R41 betyder halogen, alkyl med 1-4 carbonatomer, trifluormethyl eller nitro, og den anden betyder hydro-30 gen, med undtagelse af at R^ ikke kan være methyl, når R3' er brom, ved omsætning med ammoniak eller aminer med formlen 35
DK 154081 B
4 m^1 111 \s2 5 hvori Ri og R2 har den ovenstående betydning, i et inert 10 opløsningsmiddel.
Forbindelserne med formlen Ila kan også først omdannes til hidtil ukendte 3-halogen-l-benzoxepin-5(2H)-on-for-bindelser med den almene formel 15
O
20 IV a hvori R31 og R^j' har den ovenstående betydning, og X 25 betyder chlor eller brom, ved omsætning med et tilsvarende syrehalogenid, og forbindelserne med formlen IVa derpå omsættes med ammoniak eller aminerne med formlen III i et inert opløsningsmiddel.
30 Omsætningen af en forbindelse med formlen Ila eller IVa med ammoniak eller amin med formlen III kan foregå på i og for sig kendt måde. Omsætningen af 2,3,4,5-tetrahy-dro-l-benzoxepin-3,5-dion-forbindelsen med formlen Ila med ammoniak eller aminerne med formlen III kan fremmes 35 5
DK 154081 B
ved tilsætning af katalytiske mængder af uorganiske eller organiske syrer, som f.eks. saltsyre, svovlsyre, p-toluensulfonsyre eller myresyre. Som inerte opløsningsmidler kan f.eks. anvendes chloroform, dichlor-5 methan, benzen eller toluen. Reaktionen kan gennemføres i temperaturområdet fra 0 til 150 °C. Omsætningen kan forbedres ved, at man under reaktionen på sædvanlig måde fjerner det dannede vand. Omsætningen af forbindelserne med formlen IVa med ammoniak eller aminerne med formlen 10 III kan gennemføres i et inert opløsningsmiddel, såsom chloroform, dichlormethan, dimethylformamid, dioxan eller tetrahydrofuran, ved temperaturer mellem -70 og 50 °C, hvorved reaktionen fortrinsvis gennemføres i nærvær af en organisk base, såsom triethylamin eller en over-15 skydende mængde af ammoniak eller den anvendte amin..
Som syrehalogenider til fremstilling af forbindelserne med formlen IVa kommer phosphoroxidhalogenider, phos-phortrihalogenider, thionylchlorid eller især oxalyl-20 chlorid på tale. I nærvær af et inert opløsningsmiddel f.eks. dichlormethan eller dimethylformamid, kan omsætningen gennemføres i temperaturområdet fra -20 til 80 °C. Til omsætningen med ammoniak eller med formlen III kan det for overskydende syrehalogenid og for opløs-25 ningsmiddel befriede reaktionsprodukt med formlen IVa anvendes.
Opfindelsen belyses nærmere ved de efterfølgende eksempler, hvoraf eksempel 1-3 viser fremstillingen af for-30 bindeiserne med formlen Ila ifølge opfindelsen, og eksempel 4 og 5 viser anvendelsen af disse til fremstilling af de farmakologisk aktive forbindelser med formlen la.
35
DK 154081 B
6 EKSEMPEL 1
Til en opløsning af 242 g (1 mol) (2'-acetyl-4'-chlor)-phenoxyeddikesyre-methylester i 300 ml dimethylformamid, 5 afkølet til -20 °C, sættes 30,1 g (1 mol) natriumhydrid (80% i olie) under afkøling i små portioner, således at temperaturen ikke stiger over -10 °C. Derpå omrøres i 45 minutter ved -15 °C, hvorpå opløsningen forsigtigt hældes ud i isvand og ekstraheres en gang med toluen. Efter 10 syrning af den vandige fase frafiltreres det udfældende produkt ved sugning og omkrystalliseres fra cyclohe-xan/toluen. Der opnås 126 g (60%) 2,3,4,5-tetrahydro-7-chlor-l-benzoxepin-3,5-dion med smp. 131-134 °C.
15 EKSEMPEL 2
Til en opløsning af 28,7 g (0,1 mol) (2'-acetyl-4'-brom)-phenoxyeddikesyre-methylester i 150 ml tørt te-trahydrofuran dryppes 8,8 g (0,11 mol) lithium-tert.-20 butoxid i 50 ml tørt tetrahydrofuran under afkøling, således at temperaturen holdes mellem 25 og 35 °C. Derpå hældes suspensionen i 400 ml petroleumsether, og det udfældede lithiumsalt af 2,3,4,5-tetrahydro-7-brom-l-ben-zoxepin-3,5-dion frafiltreres ved sugning. Dette salt 25 indføres i en blanding af 150 ml vand og 11 ml saltsyre (32%). Det udfældede produkt frafiltreres ved sugning, opløses i dichlormethan, og opløsningen vaskes med mættet kogsaltopløsning, tørres over natriumsulfat, inddampes, og remanensen omkrystalliseres fra cyclohexan. Der 30 blev opnået 11,7 g (46%) 2,3,4,5-tetrahydro-7-brom-l-benzoxepin-3,5-dion med smp. 110-112 °C.
35
BK 154081B
7 EKSEMPEL 3 På den i eksempel 1 og 2 beskrevne måde fremstillas under anvendelse af natir iumhyd rid eller 1 i thi um- teafct. -5 butoxid ud fra henholdsvis (2'-acetyl-4'methyl)-phenoxyeddikesyre-methylester„ (2 '-acetyl-5' -methyl) -jftienoxyeddikesyre-methylester,, {2'-acetyl-5'-chlor) phenoxyeddikesyre-methylester,, 10 (2' -<acetyl-4 * -fluor) -phenoxyeddikesyre-methylester,, (2' -acetyl-4', 5' -dichlox) -phenoxyeddikesyre-methylester, (2' -acetyl-4'-chlor-5'methyl)-phenoxyeddikesyre-mefihyl-ester, (2'-acetyl-4', 5'-dimethyl)-phenoxyeddikesyre-methyl— 15 ester, t (2' -acetyl-5'-tert.-butyl)-phenoxyeddikesyre-methyl-ester, (2'-acetyl-4'-ethyl)-phenoxyeddikesyre-methylester ootg (2'-acetyl-4'-nitro)-phenoxyeddikesyre-methylester 20 i lignende udbytter forblindelserne:
Smp„ °C
2.3.4.5- tetrahydro-7-methyl-l- 25 benzoxepin-3,5-dion 124-127 2.3.4.5- tetrahydro-8-methyl-l- benzoxepin-3,5-dion 97-598 30 2,3,4,5-tetrahydro-8- chlor-l-benzoxepin-3,5-dion 152-154 2.3.4.5- tetrahydro -7- fluor-l-benzoxepin-3,5-dion 138-140 35
DK 154081 B
8 2.3.4.5- tetrahydro-7,8- dichlor-l-benzoxepin-3,5-dion 168-170 5 2,3,4,5-tetrahydro-7- chlor-8-methyl-l-benzoxepin-3,5-dion 172-174 2.3.4.5- tetrahydro-7,8- dimethyl-l-benzoxepin-3,5-dion 117-118 10 2.3.4.5- tetrahydro-8-tert.-butyl-l-benzoxe- pin-3,5-dion IR(CH2Cl2):1676, 1738 cm"1 olie 2.3.4.5- tetrahydro-7- 15 ethyl-l-benzoxepin-3,5-dion 74-75 2.3.4.5- tetrahydro-7- nitro-l-benzoxepin-3,5-dion 138-139 20 EKSEMPEL 4 I en opløsning af 57,1 g (0,3 mol) 2,3,4,5-tetrahydro-7-methyl-l-benzoxepin-3,5-dion og en spatelspids p-toluen-sulfonsyre i 225 ml dimethylformamid ved 100 °C indledes 25 methylamin under omrøring. Reaktionsblandingen omrøres i 30 minutter til afslutning af reaktionen. Derefter inddampes opløsningen, remanensen tilsættes vand og filtreres, og det opnåede rå produkt omkrystalliseres fra ed-dikesyreethylester. Der opnås 54,8 g 3-methylamino-7-me-30 thyl-l-benzoxepin-5(2H)-on med et smeltepunkt på 178-180 °C.
EKSEMPEL 5 35 ΕΚ 154081 Β 9 hhv.
2,3,4,5-tet rahydro-7-f!>uor-l-benzoxepin-3,5-dion-, 2,3/4,5-tetrahydro-7,8-Tdichlor-l-benzoxepin-3, 5-etion, 2,3/4,5-tetrahydro-7,8-dimethyl-l-benzoxepin-3,SrSion, 5 2,3/4,5-tet rahydro-7-br<om-l-rbenzoxepin-3,5-dion, 2,3/4,5-tetrahydro-7-dtalor-l-benzoxepin-, 3,5-dion-/ 2,3/4,5-tetrahydro-8-cblor-l-benzoxepin-3,5-dion, 2,3/4,5-tetrahydro-7-et!hyl-l-benzoxepin-3,5-dion, 2,3-, 4,5-tetrahydro-8-methyl-l-benzoxepin-3,5-dion,/ 10 2,3/4,5-tetrahydro-7-chlor-8-methyl-l-benzoxepin-3J^5 -dion, 2,3/4,5-tetrahydro-8-tert.-butyl-l-benzoxepin-3,5-diion og 2,3/4,5-tet rahydro-7-nilaro-l-benzoxepin-3,5-dion 15 og methylamin eller dinælthylamin med lignende udbybfcer forbindelserne:
Smp.. °C
3-methylamino-7-f luor-l-lbenzoxepin-5 (2H) -on (.0,25 H20) 2035-219 20 3-methylamino-7,8-dichlo.x— 1-benzoxepin- 5(2H$-on 2228—241 3-methylamino-7,8-dimethyl-l-benzoxepin-5(2H|—on 21B-222 3-methylamino-7-brom-l-benzoxepin-5( 2H)-on 2000-202 25 3-methylamino-7-chlor-l—benzoxepin-5(2H)-on 113.6-198 3-methylamino-8-chlor-l-ibenzoxepin-5( 2H)-on 20:4-208 3-methylamino-7-ethyl-l-benzoxepin-5(2H)-on 1181-183 3-dimethylamino-8-chlor.-l-benzoxepin-5( 2H)-on 326-129 3-methylamino-7-chlor-8-,methyl-l-benzoxepin-30 5(2H)-on 229-234 3-methylamino-8-methyl-l-benzoxepin-5(2H)-on 182-184 3-methylamino-8-tert.-hatyl-l-benzoxepin-5(2H)-on 195-196 3-methylamino-7-nitro-l-benzoxepin-5(2H)-on 200.
35
Claims (1)
10 R >\Λλ / hvori R3' og R4' hver for sig betyder halogen eller alkyl med 1-4 carbonatomer, eller en af R3' og R^ betyder 15 halogen, alkyl med 1-4 carbonatomer, trifluormethyl eller nitro, og den anden betyder hydrogen, med undtagelse af at R4' ikke kan være methyl, når R3'er brom. 20 25 30 35
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2931398 | 1979-08-02 | ||
| DE19792931398 DE2931398A1 (de) | 1979-08-02 | 1979-08-02 | Neue 1-benzoxepin-5(2h)-on-derivate und ihre salze, verfahren und zwischenprodukte zu deren herstellung und diese verbindungen enthaltende arzneimittel |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK86188A DK86188A (da) | 1988-02-19 |
| DK86188D0 DK86188D0 (da) | 1988-02-19 |
| DK154081B true DK154081B (da) | 1988-10-10 |
| DK154081C DK154081C (da) | 1989-02-27 |
Family
ID=6077477
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK333280A DK151629C (da) | 1979-08-02 | 1980-08-01 | Analogifremgangsmaade til fremstilling af 3-amino-1-benzoxepin-5(2h)-on-derivater eller syreadditionssalte deraf |
| DK086188A DK154081C (da) | 1979-08-02 | 1988-02-19 | 2,3,4,5-tetrahydro-1-benzoxepin-3,5-dion-forbindelser |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK333280A DK151629C (da) | 1979-08-02 | 1980-08-01 | Analogifremgangsmaade til fremstilling af 3-amino-1-benzoxepin-5(2h)-on-derivater eller syreadditionssalte deraf |
Country Status (20)
| Country | Link |
|---|---|
| US (2) | US4279905A (da) |
| EP (2) | EP0025109B1 (da) |
| JP (2) | JPS5653675A (da) |
| AU (1) | AU537110B2 (da) |
| CA (1) | CA1162553A (da) |
| DD (2) | DD154487A5 (da) |
| DE (3) | DE2931398A1 (da) |
| DK (2) | DK151629C (da) |
| ES (2) | ES8107212A1 (da) |
| FI (1) | FI77029C (da) |
| GR (1) | GR69360B (da) |
| HU (2) | HU182436B (da) |
| IE (1) | IE50059B1 (da) |
| IL (1) | IL60557A (da) |
| NO (1) | NO155054C (da) |
| NZ (1) | NZ194331A (da) |
| PH (2) | PH16306A (da) |
| PT (1) | PT71599A (da) |
| SU (2) | SU955860A3 (da) |
| ZA (1) | ZA804546B (da) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3440296A1 (de) * | 1984-11-05 | 1986-05-15 | Kali-Chemie Pharma Gmbh, 3000 Hannover | 3-amino-2,3-dihydro-1-benzoxepin-verbindungen sowie verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel |
| DE3440295A1 (de) * | 1984-11-05 | 1986-05-15 | Kali-Chemie Pharma Gmbh, 3000 Hannover | Verfahren zur diastereoselektiven reduktion von 3-amino-1-benzoxepin-5(2h)-onen |
| GB0412139D0 (en) | 2004-06-01 | 2004-06-30 | Exxonmobil Chem Patents Inc | Olefin oligomerization process |
| JP4916481B2 (ja) * | 2008-05-27 | 2012-04-11 | ティーオーエー株式会社 | 機器筐体 |
| WO2010077976A2 (en) | 2008-12-17 | 2010-07-08 | The Regents Of The University Of California | Prokineticin receptor antagonists and uses thereof |
| RU2012106505A (ru) | 2009-08-31 | 2013-08-27 | Сони Корпорейшн | Устройство передачи сигналов, электронное устройство и способ передачи сигналов |
| WO2019118230A1 (en) | 2017-12-14 | 2019-06-20 | Exxonmobil Chemical Patents Inc. | Processes for isomerizing alpha olefins |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1593760A1 (de) * | 1967-02-01 | 1972-06-08 | Boehringer Sohn Ingelheim | Verfahren zur Herstellung neuer Benz-epinderivate |
| US3991082A (en) * | 1975-03-03 | 1976-11-09 | Warner-Lambert Company | 4-Substituted-2,3-dihydro-1-benzoxepin-3,5-diones and tautomers |
| US4153612A (en) * | 1977-10-31 | 1979-05-08 | The Upjohn Company | 2-Benzoxepins |
-
1979
- 1979-08-02 DE DE19792931398 patent/DE2931398A1/de not_active Withdrawn
-
1980
- 1980-07-03 IE IE1387/80A patent/IE50059B1/en unknown
- 1980-07-11 NZ NZ194331A patent/NZ194331A/xx unknown
- 1980-07-11 IL IL60557A patent/IL60557A/xx unknown
- 1980-07-14 AU AU60389/80A patent/AU537110B2/en not_active Ceased
- 1980-07-16 PH PH24299A patent/PH16306A/en unknown
- 1980-07-24 PT PT71599A patent/PT71599A/pt unknown
- 1980-07-25 SU SU802950853A patent/SU955860A3/ru active
- 1980-07-28 ZA ZA00804546A patent/ZA804546B/xx unknown
- 1980-07-28 US US06/173,076 patent/US4279905A/en not_active Expired - Lifetime
- 1980-07-29 DE DE8080104466T patent/DE3070642D1/de not_active Expired
- 1980-07-29 EP EP80104466A patent/EP0025109B1/de not_active Expired
- 1980-07-29 DE DE8282108303T patent/DE3070495D1/de not_active Expired
- 1980-07-29 HU HU821782A patent/HU182436B/hu unknown
- 1980-07-29 HU HU801890A patent/HU181580B/hu unknown
- 1980-07-29 EP EP82108303A patent/EP0074121B1/de not_active Expired
- 1980-07-30 DD DD80222971A patent/DD154487A5/de unknown
- 1980-07-30 DD DD80237321A patent/DD201792A5/de unknown
- 1980-07-30 FI FI802385A patent/FI77029C/fi not_active IP Right Cessation
- 1980-07-31 GR GR62578A patent/GR69360B/el unknown
- 1980-08-01 JP JP10515980A patent/JPS5653675A/ja active Granted
- 1980-08-01 NO NO802324A patent/NO155054C/no unknown
- 1980-08-01 ES ES493927A patent/ES8107212A1/es not_active Expired
- 1980-08-01 CA CA000357544A patent/CA1162553A/en not_active Expired
- 1980-08-01 DK DK333280A patent/DK151629C/da not_active IP Right Cessation
-
1981
- 1981-03-16 US US06/243,745 patent/US4320061A/en not_active Expired - Lifetime
- 1981-04-09 ES ES501213A patent/ES8203875A1/es not_active Expired
- 1981-06-11 SU SU813294901A patent/SU963468A3/ru active
- 1981-11-27 PH PH26551A patent/PH17306A/en unknown
-
1988
- 1988-02-19 DK DK086188A patent/DK154081C/da active
-
1989
- 1989-03-16 JP JP1062356A patent/JPH0256478A/ja active Granted
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