NO157451B - Et nytt utgangsmateriale, norskopin, og syreaddisjonssalter derav. - Google Patents
Et nytt utgangsmateriale, norskopin, og syreaddisjonssalter derav. Download PDFInfo
- Publication number
- NO157451B NO157451B NO831446A NO831446A NO157451B NO 157451 B NO157451 B NO 157451B NO 831446 A NO831446 A NO 831446A NO 831446 A NO831446 A NO 831446A NO 157451 B NO157451 B NO 157451B
- Authority
- NO
- Norway
- Prior art keywords
- norskopin
- acid addition
- addition salts
- output material
- new output
- Prior art date
Links
- 150000003839 salts Chemical class 0.000 title claims description 6
- 239000002253 acid Substances 0.000 title claims description 3
- -1 NORSKOPIN Substances 0.000 title description 2
- 239000000463 material Substances 0.000 title 1
- MOYZEMOPQDTDHA-YQYZCKNZSA-N norhyoscine Chemical compound C1([C@H](C(=O)OC2C[C@@H]3N[C@@H]([C@H]4O[C@H]43)C2)CO)=CC=CC=C1 MOYZEMOPQDTDHA-YQYZCKNZSA-N 0.000 abstract description 2
- 238000003776 cleavage reaction Methods 0.000 abstract 1
- 150000004678 hydrides Chemical class 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- 239000012442 inert solvent Substances 0.000 abstract 1
- MOYZEMOPQDTDHA-UHFFFAOYSA-N norscopolamine Natural products C1C(C2OC22)NC2CC1OC(=O)C(CO)C1=CC=CC=C1 MOYZEMOPQDTDHA-UHFFFAOYSA-N 0.000 abstract 1
- 230000007017 scission Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 238000007327 hydrogenolysis reaction Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000001078 anti-cholinergic effect Effects 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000001813 broncholytic effect Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
- C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
- C07D451/06—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pulmonology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Crystals, And After-Treatments Of Crystals (AREA)
- Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
- Steroid Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Financial Or Insurance-Related Operations Such As Payment And Settlement (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Treatments For Attaching Organic Compounds To Fibrous Goods (AREA)
- Control Of Motors That Do Not Use Commutators (AREA)
- Liquid Deposition Of Substances Of Which Semiconductor Devices Are Composed (AREA)
- Physical Deposition Of Substances That Are Components Of Semiconductor Devices (AREA)
- Forklifts And Lifting Vehicles (AREA)
Description
Denne oppfinnelsen angår den nye forbindelse norskopin med formelen
og syreaddisjonssalter derav,
Norskopin er et verdifullt utgangsmateriale, f.eks. for fremstilling av nye 6,11-dihydro-dibenzo-[b,e]-tiepin-11-N-alkyl-norskopinetere med den generelle formel II
hvor R er en lineær eller forgrenet alkylrest med 1-10 karbon-atomer, og ^ betyr et farmakologisk godtagbart anion, f.eks.
et halogenatom eller resten av en organisk sulfonsyre. Disse forbindelser er verdifulle farmasøytika med et godt avpasset forhold mellom anticholinerg og antihistaminisk virkning.
De egner seg derfor meget godt for anvendelse som bronkolytika. Disse forbindelser er beskrevet i patentansøkning 83.1084.
Viderebearbeidelsen av norskopin til norskopinetrene med den ovenfor angitte formel II kan foretas ved at man først, f.eks. ved vanlig N-alkylering med alkylhalogenider, fremstiller N-alkylnorskopinene med den generelle formel III
hvor R har den ovenfor angitte betydning, og disse fremstilles med forbindelser med den generelle formel IV hvor X er en lett avspaltbar gruppe (f.eks. et halogenatom), for å danne tertiære forbindelser med den generelle formel V
hvor R har den ovenfor angitte betydning, og sistnevnte omsettes med vanlige metyleringsmidler med den generelle formel VI
CH3 - X VI
hvor X har den ovenfor angitte betydning, for å danne de kvartære salter med den generelle formel II. Med hensyn til nærmere enkeltheter ved viderebearbeidelsen til forbindelsene med den generelle formel II henvises til ovennevnte patentansøkning 83.1084.
Fremstillingen av norskopin skjer ved at man behandler norskopolamin resp. salter derav med egnede komplekse metall-hydrider (fortrinnsvis ved romtemperatur eller lavere temperaturer) i et oppløsningsmiddel. Spesielt egnet er metall-borhydrider, og av disse særlig natriumborhydrid (NaBH^).
Også litiumalanat kan prinsipielt anvendes, men for å unngå bireaksjoner bør det her anvendes temperaturer fra 0°C og under.
Som oppløsningsmiddel for den ovenfor angitte omsetning kommer først og fremst etanol i betraktning. Høyere alkoholer og andre organiske oppløsningsmidler (f.eks. etere) er mindre gunstige, da norskopolaminsaltene som fortrinnsvis anvendes som utgangsmaterialer, er tungtløselige i disse. Også metanol er bare mindre egnet, da det f.eks. spalter natriumborhydrid meget raskt allerede ved 0°C, slik at den anvendte mengde av dette stoff blir unødig stor. Også i vann kan det skje hydrogenolyse, f.eks. når pH innstilles på 6-7. Den påfølgende isolering av norskopin fra vann er imidlertid mer besværlig enn isoleringen fra etanol.
Fremstillingen av det som utgangsmateriale anvendte norskopolamin er beskrevet i DE-AS 1 670 257 og 1 670 258.
Det følgende eksempel illustrerer oppfinnelsen ytterligere.
Eksempel
Norskopin resp, norskopin- hydroklorid
32,6 g (0,1 mol) norskopolamin-hydroklorid suspenderes i 350 ml etanol, og ved en temperatur på 20°C under stadig om-røring tilsettes 3,78 g (0,1 mol) natriumborhydrid i seks porsjoner med 20 minutters mellomrom. Man lar det hele efter-reagere i 12 timer. Hydrogenolysen er efter denne tid avsluttet. Ved -5 til -10°C under nitrogenatmosfære innføres hydrogenklorid-gass inntil man får sur reaksjon, og oppløsningen vaskes fri for hydrogenklorid med 1,5 liter eter. Krystallene som utgnies fint efter tørring, suspenderes i 2 liter metylenklorid, oppvarmes til kokning, og i den kokende metylenklorid innføres ammoniakk for å danne basen inntil fullstendig omsetning. Efter fraskil-lelse av de organiske salter avdestilleres metylenklorid under redusert trykk ved 30°C.
Norskopin krystalliserer i farveløse krystaller.
Smeltepunkt 198-202°C (dekomp.)
Utbytte: 12,0 g (85,7% av det teoretiske).
Hydrokloridet kan fremstilles på vanlig måte.
Farveløse krystaller (etanol), smeltepunkt 292-293°C (dekomp.), omvandlingspunkt ~ 205°C.
Ved elementæranalyse og spektra bekreftes at denne forbindelse foreligger.
Claims (1)
- Norskopin, karakterisert ved formel I og syreaddisjonssalter derav.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19823215490 DE3215490A1 (de) | 1982-04-26 | 1982-04-26 | Neues vorprodukt, verfahren zu seiner herstellung und seine verwendung |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO831446L NO831446L (no) | 1983-10-27 |
| NO157451B true NO157451B (no) | 1987-12-14 |
| NO157451C NO157451C (no) | 1988-03-23 |
Family
ID=6161960
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO831446A NO157451C (no) | 1982-04-26 | 1983-04-25 | Et nytt utgangsmateriale, norskopin, og syreaddisjonssalter derav. |
Country Status (23)
| Country | Link |
|---|---|
| US (1) | US4755603A (no) |
| EP (1) | EP0093343B1 (no) |
| JP (1) | JPS58201778A (no) |
| KR (1) | KR900004128B1 (no) |
| AT (1) | ATE18401T1 (no) |
| AU (1) | AU557702B2 (no) |
| CA (1) | CA1254565A (no) |
| CS (1) | CS236793B2 (no) |
| DD (1) | DD209631A5 (no) |
| DE (2) | DE3215490A1 (no) |
| DK (1) | DK160305C (no) |
| ES (1) | ES521808A0 (no) |
| FI (1) | FI72976C (no) |
| GR (1) | GR78838B (no) |
| HU (1) | HU193162B (no) |
| IE (1) | IE55356B1 (no) |
| IL (1) | IL68478A0 (no) |
| NO (1) | NO157451C (no) |
| NZ (1) | NZ203979A (no) |
| PL (1) | PL138641B1 (no) |
| PT (1) | PT76583B (no) |
| YU (1) | YU43827B (no) |
| ZA (1) | ZA832882B (no) |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3211185A1 (de) * | 1982-03-26 | 1983-09-29 | Boehringer Ingelheim KG, 6507 Ingelheim | Neue quartaere 6,11-dihydro-dibenzo-(b,e)-thiepin-11-n-alkyl- norscopinether und verfahren zu deren herstellung |
-
1982
- 1982-04-26 DE DE19823215490 patent/DE3215490A1/de not_active Withdrawn
-
1983
- 1983-04-13 FI FI831233A patent/FI72976C/fi not_active IP Right Cessation
- 1983-04-20 DD DD83250032A patent/DD209631A5/de not_active IP Right Cessation
- 1983-04-21 GR GR71158A patent/GR78838B/el unknown
- 1983-04-21 PT PT76583A patent/PT76583B/pt not_active IP Right Cessation
- 1983-04-22 NZ NZ203979A patent/NZ203979A/en unknown
- 1983-04-22 AT AT83103936T patent/ATE18401T1/de not_active IP Right Cessation
- 1983-04-22 EP EP83103936A patent/EP0093343B1/de not_active Expired
- 1983-04-22 DE DE8383103936T patent/DE3362384D1/de not_active Expired
- 1983-04-25 HU HU831416A patent/HU193162B/hu not_active IP Right Cessation
- 1983-04-25 CA CA000426596A patent/CA1254565A/en not_active Expired
- 1983-04-25 PL PL1983241634A patent/PL138641B1/pl unknown
- 1983-04-25 ZA ZA832882A patent/ZA832882B/xx unknown
- 1983-04-25 ES ES521808A patent/ES521808A0/es active Granted
- 1983-04-25 NO NO831446A patent/NO157451C/no unknown
- 1983-04-25 JP JP58072765A patent/JPS58201778A/ja active Granted
- 1983-04-25 CS CS832918A patent/CS236793B2/cs unknown
- 1983-04-25 IE IE937/83A patent/IE55356B1/en not_active IP Right Cessation
- 1983-04-25 IL IL68478A patent/IL68478A0/xx not_active IP Right Cessation
- 1983-04-25 YU YU937/83A patent/YU43827B/xx unknown
- 1983-04-25 DK DK182083A patent/DK160305C/da not_active IP Right Cessation
- 1983-04-25 KR KR1019830001743A patent/KR900004128B1/ko not_active Expired
- 1983-04-26 AU AU13946/83A patent/AU557702B2/en not_active Ceased
-
1987
- 1987-05-26 US US07/053,956 patent/US4755603A/en not_active Expired - Fee Related
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