DK151012B - Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-aminooxymethyl-isoxazoler eller et syreadditionssalt deraf - Google Patents
Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-aminooxymethyl-isoxazoler eller et syreadditionssalt deraf Download PDFInfo
- Publication number
- DK151012B DK151012B DK122581AA DK122581A DK151012B DK 151012 B DK151012 B DK 151012B DK 122581A A DK122581A A DK 122581AA DK 122581 A DK122581 A DK 122581A DK 151012 B DK151012 B DK 151012B
- Authority
- DK
- Denmark
- Prior art keywords
- methyl
- acid addition
- addition salt
- aminooxymethyl
- isoxazoles
- Prior art date
Links
- 239000002253 acid Substances 0.000 title claims description 7
- 238000000034 method Methods 0.000 title claims description 7
- 150000003839 salts Chemical class 0.000 title claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 18
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 238000001953 recrystallisation Methods 0.000 description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000001077 hypotensive effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- HWYOAIMOZXZKCI-UHFFFAOYSA-N 2-[(2-bromo-4-chloro-3-methyl-3H-1,2-oxazol-5-yl)methoxy]isoindole-1,3-dione Chemical compound CC1N(OC(=C1Cl)CON1C(C=2C(C1=O)=CC=CC=2)=O)Br HWYOAIMOZXZKCI-UHFFFAOYSA-N 0.000 description 2
- PVFOHMXILQEIHX-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-bromophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Br PVFOHMXILQEIHX-UHFFFAOYSA-N 0.000 description 2
- USVZHTBPMMSRHY-UHFFFAOYSA-N 8-[(6-bromo-1,3-benzodioxol-5-yl)sulfanyl]-9-[2-(2-chlorophenyl)ethyl]purin-6-amine Chemical compound C=1C=2OCOC=2C=C(Br)C=1SC1=NC=2C(N)=NC=NC=2N1CCC1=CC=CC=C1Cl USVZHTBPMMSRHY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-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
- 241000699670 Mus sp. Species 0.000 description 2
- 206010030113 Oedema Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000001741 anti-phlogistic effect Effects 0.000 description 2
- 230000001754 anti-pyretic effect Effects 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000007787 solid 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
- CFMZSMGAMPBRBE-UHFFFAOYSA-N 2-hydroxyisoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(O)C(=O)C2=C1 CFMZSMGAMPBRBE-UHFFFAOYSA-N 0.000 description 1
- JUXRBAWKRIAKHJ-UHFFFAOYSA-N CC1=NOC(=C1Cl)C(Br)Br Chemical compound CC1=NOC(=C1Cl)C(Br)Br JUXRBAWKRIAKHJ-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- GPJSFIJJJSFUCG-UHFFFAOYSA-N Cl.CC1=NOC(=C1Cl)C(ON)Br Chemical compound Cl.CC1=NOC(=C1Cl)C(ON)Br GPJSFIJJJSFUCG-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- DJWDPWYBHUQKNT-UHFFFAOYSA-N O-[(4-bromo-3-methyl-1,2-oxazol-5-yl)methyl]hydroxylamine Chemical compound CC1=NOC(CON)=C1Br DJWDPWYBHUQKNT-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- CJCSPKMFHVPWAR-JTQLQIEISA-N alpha-methyl-L-dopa Chemical compound OC(=O)[C@](N)(C)CC1=CC=C(O)C(O)=C1 CJCSPKMFHVPWAR-JTQLQIEISA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 150000001804 chlorine Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- KGVPNLBXJKTABS-UHFFFAOYSA-N hymexazol Chemical compound CC1=CC(O)=NO1 KGVPNLBXJKTABS-UHFFFAOYSA-N 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 150000002545 isoxazoles Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011814 protection agent Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
151012 o
Det er kendt, at 3-hydroxy-5-methylisoxazol kan anvendes som plantebeskyttelsesmiddel (Merck index, 9.
(1961), side 123). Delvis mættede isoxazolderivater, der anvendes som tumorundertrykkende midler, er beskrevet i 5 Tetrahedron Letters 2549 (1973) og i J. Antib. 28A, 91 (1975).
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte 3-methyl- . -4-halogen-.5-aminooxymethyl-isoxazoler med den almene 10 formel (I)
CH, R
"W
N II
15 ^ O CH2ONH2 hvori R2 står for et halogenatom, eller et farmaceutisk acceptabelt syreadditionssalt deraf.
Disse forbindelser med formel (I) er nyttige til 20 anvendelse som farmaceutika, da de har hypotensiv, antiphlo-gistisk og antipyretisk virkning. Til forskel fra kendte forbindelser kan de tillige indgives såvel oralt som intravenøst.
Foretrukne repræsentanter for de hidtil ukendte 25 forbindelser med den almene formel (I) er de, hvori R2 er chlor.
Syreadditionssaltene af forbindelserne med den almene formel (I) kan dannes med farmaceutisk acceptable uorganiske eller organiske syrer (f.eks. saltsyre, hydro-30 genbromidsyre, svovlsyre, phosphorsyre, vinsyre, fumarsyre, maleinsyre eller citronsyre) .
Den her omhandlede analogifremgangsmåde er karakteriseret ved, at man omsætter en forbindelse med den almene formel (Id) 35
O
2 151012 CH3 R2 XX^/V)
II
o hvori R2 er som defineret ovenfor, med hydrazinhydrat og om øn-10 sket omdanner en således opnået forbindelse med den almene formel (I) til et farmaceutisk acceptabelt syreadditions-salt deraf.
Ved fremgangsmåden ifølge den foreliggende opfindelse omsættes en forbindelse med den almene formel (Id) 15 med hydrazinhydrat. Reaktionen udføres i et organisk opløsningsmiddel. Chlorerede carbonhydrider (f.eks. dichlormethan, dichlorethan eller chloroform) anvendes fortrinsvis til dette formål. Reaktionens temperatur kan varieres fra ca. 20°C til reaktionsblandingens kogepunkt. Slutproduktet kan for-20 trinsvis omdannes til dets hydrochlorid med saltsyre.
De hidtil ukendte forbindelser fremstillet ved fremgangsmåden ifølge den foreliggende opfindelse udviser en stærk hypotensiv virkning, og visse af forbindelserne udøver også antiphlogistiske og antipyretiske virkninger.
25 Når en tiendedel af LD^g-dosen af 3-methyl-4- -brom-5-aminooxymethyl-isoxazol bestemt intravenøst på mus indgives intravenøst til bedøvede katte, iagttages der en stor hypotensiv virkning med kort varighed. Fordelen ved de hidtil ukendte forbindelser fremstillet ifølge opfindelsen 30 er., at de er virksomme, hvad enten de indgives oralt eller intravenøst, medens L-a-methyl-dopa kun er aktivt, når det indgives intravenøst.
Den antiinflammatoriske virkning af de hidtil ukendte forbindelser fremstillet ifølge den foreliggende opfindel-35 se bestemmes ligeledes. En tiendedel af LD^g-dosen (intravenøst, på mus) indgives rotter, og inhiberingen af ødemet, fremkaldt af lokalindgivelse af (0,05 ml/3 mg dextran, bestemmes.
Herved opnås med det i eksemplet beskrevne chlorderivat en inhibe- 3 151012
O
ring af ødemet på 38%.
De fremstillede forbindelser anvendes i farmaceutiske præparater, der som aktivt middel indeholder en forbindelse med den almene formel (I) eller et farmaceutisk 5 acceptabelt syreadditionssalt deraf og et egnet indifferent ikke-toksisk, fast eller flydende farmaceutsk bærestof.
Bærestofferne kan være sådanne, som sædvanligvis anvendes i farmacien (f.eks. calciumcarbonat, magnesiumstea-rat, vand, polyalkylenglycol eller stivelse). Ovennævnte 10 farmaceutiske præparater kan formuleres ved hjælp af kendte metoder i fast form (f.eks. tabletter, kapsler, dragées eller stikpiller) eller flydende form (f.eks. opløsninger, suspensioner eller emulsioner).
Den daglige dosis af forbindelserne med den almene 15 formel (I) afhænger af forskellige faktorer (f.eks. den givne forbindelses aktivitet, patientens tilstand, etc.) og bestemmes altid af lægens forordninger.
Den foreliggende opfindelse er illustreret ved hjælp af det følgende eksempel.
20
Eksempel
Fremstilling af 3-methyl-4-chlor(brom)-5-aminooxymethyl--isoxazolhydrochlorid 25 0,14 mol 3-methyl-4-chlor(brom)-5-(phthalimido- -oxymethyl)-isoxazol opløses i 500 ml vandfrit dichlormethan eller dichlorethan, derefter tilsættes 60 g 98%'s hydrazinhydrat, og opløsningen omrøres ved stuetemperatur i 16-20 timer. Det fraskilte phthaloyl-hydrazid opløses, vaskes 30 med dichlorethan,- og filtratet, som er kombineret med vaskevæsken, inddampes. Remanensen opløses i 200 ml vandfri ether, opløsningen tørres over magnesiumsulfat, koncentreres til 1/3 af den tidligere vægt og mættes med vandfrit hydrogen-chlorid. Det udskilte produkt filtreres fra, vaskes med 35 vandfri ether og omkrystalliseres.
151012 4
O
Chlorderivat:
Udbytte: 87%
Smp.ϊ 198-200°C
Omkrystallisation: fra vandfrit ethanol.
5 Analyse:
Beregnet: C = 30,17%, H = 4,05%, N = 14,08%, Cl = 17,81%^
Cl" = 17,81%.
Fundet: C = 30,02%, H = 3,99%, N = 14,06%, Cl = 17,77%;
Cl" = 17,78.
10
Bromderivat:
Udbytte: 8 3 %
Smp.: 180-182°C
15 Omkrystallisation: fra vandfrit ethanol.
Analyse:
Beregnet: C = 24,66%, H = 3,11%, N = 11,5%, Cl" = 14,56%,
Br = 32,80%.
Fundet: C = 25,11%, H = 3,08%, N = 11,37%, Cl" = 14,50%^ 20 Br = 32,72%.
Fremstilling af udgangsmaterialet 3-methyl-4-chlor(brom)--5-(phthalimido-oxymethyl)-isoxazol 0,1 mol 3-methyl-4-chlor(brom)-5-brommethyl-isoxazol 25 opløses i 120 ml vandfrit N,N-dimethylformamid, derefter tilsættes 0,11 mol N-hydroxy-phthalimid og 0,11 mol tri-ethylaminjog blandingen holdes på et vandbad, der er opvarmet til 100°C. Derefter afkøles den, fortyndes med vand.og de udskilte krystaller filtreres fra, vaskes med koldt 30 vand og omkrystalliseres.
Chlorderivat:
Udbytte: 89%
Smp.: 152-153°C
35 Omkrystallisation: fra ethanol
Analyse:
Beregnet: C = 53,54%, H = 3,10%, N = 9,57%, Cl= 12,11%. Fundet: C = 53,08%, H = 2,99%, N = 9,58%, Cl = 12,15%.
5 151012
O
Bromderivat:
Udbytte: 90%
Snip.: 154-156°C.
Omkrystallisation: fra ethanol/vand.
5 Analyse:
Beregnet: C = 46,31%, H = 2,59%, N = 8,31%, Br = 23,7%. Fundet: C = 47,0%, . H = 2,59%, N = 8,25%, Br = 23,67%.
Claims (1)
- O 151012 Patentkrav . Analogifremgangsmåde til fremstilling af 3-methyl--4-halogen-5-aminooxymethyl-isoxazoler med den almene formel (X) 5 CH R9 _/2 ii in N 1 CH2ONH2 10 hvori R2 står for et halogenatom, eller et farmaceutisk acceptabelt syreadditionssalt deraf, kendetegnet ved, at man omsætter en forbindelse med den almene formel (Id) 15 CH3 R XoX ch2-o-/^Y^ <Id> 20 II o hvori R2 er som defineret ovenfor, med hydrazinhydrat og 25 om ønsket omdanner en således opnået forbindelse med den almene formel (I) til et farmaceutisk acceptabelt syreadditionssalt deraf.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU63780 | 1980-03-19 | ||
| HU8080637A HU180567B (en) | 1980-03-19 | 1980-03-19 | Method for producing derivatives of isooxazole |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK122581A DK122581A (da) | 1981-09-20 |
| DK151012B true DK151012B (da) | 1987-10-12 |
| DK151012C DK151012C (da) | 1988-07-04 |
Family
ID=10950573
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK122581A DK151012C (da) | 1980-03-19 | 1981-03-18 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-aminooxymethyl-isoxazoler eller et syreadditionssalt deraf |
| DK023087A DK151959C (da) | 1980-03-19 | 1987-01-16 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogenisoxazol-5-yl-methylenoxyguanidin eller farmakologisk acceptable syreadditionssalte deraf |
| DK023187A DK153549C (da) | 1980-03-19 | 1987-01-16 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-bromethylaminomethylisoxazoler eller farmakologisk acceptable syreadditionssalte deraf |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK023087A DK151959C (da) | 1980-03-19 | 1987-01-16 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogenisoxazol-5-yl-methylenoxyguanidin eller farmakologisk acceptable syreadditionssalte deraf |
| DK023187A DK153549C (da) | 1980-03-19 | 1987-01-16 | Analogifremgangsmaade til fremstilling af 3-methyl-4-halogen-5-bromethylaminomethylisoxazoler eller farmakologisk acceptable syreadditionssalte deraf |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS56158774A (da) |
| BE (1) | BE887954A (da) |
| CA (1) | CA1163631A (da) |
| CH (1) | CH646157A5 (da) |
| DE (1) | DE3110817A1 (da) |
| DK (3) | DK151012C (da) |
| ES (3) | ES501095A0 (da) |
| FI (1) | FI70011C (da) |
| FR (1) | FR2478634A1 (da) |
| GB (1) | GB2075009B (da) |
| HU (1) | HU180567B (da) |
| IT (1) | IT1211010B (da) |
| SE (1) | SE454695B (da) |
| SU (3) | SU1053750A3 (da) |
| YU (1) | YU42560B (da) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6100260A (en) * | 1997-04-21 | 2000-08-08 | Sumitomo Pharmaceutical Company, Limited | Isoxazole derivatives |
| ID22897A (id) * | 1997-04-21 | 1999-12-16 | Sumitomo Pharmaceutical Compan | Turunan isoksazol |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL302496A (da) * | 1962-12-22 | |||
| US3808221A (en) * | 1971-04-14 | 1974-04-30 | Hoffmann La Roche | Antiandrogenic n-(3,5-dilower alkyl-4-heterocyclic)methyl)phthalimides |
-
1980
- 1980-03-19 HU HU8080637A patent/HU180567B/hu not_active IP Right Cessation
-
1981
- 1981-03-16 BE BE1/10179A patent/BE887954A/fr not_active IP Right Cessation
- 1981-03-17 YU YU689/81A patent/YU42560B/xx unknown
- 1981-03-17 SE SE8101703A patent/SE454695B/sv not_active IP Right Cessation
- 1981-03-18 IT IT8120395A patent/IT1211010B/it active
- 1981-03-18 FI FI810838A patent/FI70011C/fi not_active IP Right Cessation
- 1981-03-18 CH CH182981A patent/CH646157A5/de not_active IP Right Cessation
- 1981-03-18 ES ES501095A patent/ES501095A0/es active Granted
- 1981-03-18 DK DK122581A patent/DK151012C/da not_active IP Right Cessation
- 1981-03-18 FR FR8105378A patent/FR2478634A1/fr active Granted
- 1981-03-18 GB GB8108545A patent/GB2075009B/en not_active Expired
- 1981-03-19 SU SU813261940A patent/SU1053750A3/ru active
- 1981-03-19 CA CA000373380A patent/CA1163631A/en not_active Expired
- 1981-03-19 DE DE19813110817 patent/DE3110817A1/de not_active Withdrawn
- 1981-03-19 JP JP4023281A patent/JPS56158774A/ja active Pending
-
1982
- 1982-04-01 SU SU823414099A patent/SU1152518A3/ru active
- 1982-04-01 SU SU823416146A patent/SU1158044A3/ru active
- 1982-04-16 ES ES511894A patent/ES511894A0/es active Granted
- 1982-04-16 ES ES511895A patent/ES8305340A1/es not_active Expired
-
1987
- 1987-01-16 DK DK023087A patent/DK151959C/da not_active IP Right Cessation
- 1987-01-16 DK DK023187A patent/DK153549C/da not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| SU1152518A3 (ru) | 1985-04-23 |
| DK151959B (da) | 1988-01-18 |
| HU180567B (en) | 1983-03-28 |
| SU1053750A3 (ru) | 1983-11-07 |
| FI70011C (fi) | 1986-09-12 |
| DK122581A (da) | 1981-09-20 |
| CA1163631A (en) | 1984-03-13 |
| GB2075009A (en) | 1981-11-11 |
| DK23187A (da) | 1987-01-16 |
| FR2478634A1 (fr) | 1981-09-25 |
| YU42560B (en) | 1988-10-31 |
| YU68981A (en) | 1983-10-31 |
| BE887954A (fr) | 1981-09-16 |
| CH646157A5 (en) | 1984-11-15 |
| ES8401758A1 (es) | 1984-01-01 |
| ES511894A0 (es) | 1984-01-01 |
| SE8101703L (sv) | 1981-09-20 |
| DK153549C (da) | 1988-12-05 |
| GB2075009B (en) | 1983-11-30 |
| SU1158044A3 (ru) | 1985-05-23 |
| SE454695B (sv) | 1988-05-24 |
| IT1211010B (it) | 1989-09-29 |
| DK23087A (da) | 1987-01-16 |
| ES511895A0 (es) | 1983-05-01 |
| ES8302674A1 (es) | 1983-02-16 |
| DE3110817A1 (de) | 1982-03-04 |
| ES8305340A1 (es) | 1983-05-01 |
| JPS56158774A (en) | 1981-12-07 |
| FR2478634B1 (da) | 1983-11-10 |
| ES501095A0 (es) | 1983-02-16 |
| FI810838L (fi) | 1981-09-20 |
| FI70011B (fi) | 1986-01-31 |
| DK153549B (da) | 1988-07-25 |
| DK151959C (da) | 1988-07-11 |
| DK151012C (da) | 1988-07-04 |
| IT8120395A0 (it) | 1981-03-18 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |