NO158016B - Fremgangsmaate for fremstilling av (-)-2-(1-(2,6-diklor-fenoksy)-etyl)-1,3-diazacyklopent-2-en. - Google Patents
Fremgangsmaate for fremstilling av (-)-2-(1-(2,6-diklor-fenoksy)-etyl)-1,3-diazacyklopent-2-en. Download PDFInfo
- Publication number
- NO158016B NO158016B NO824148A NO824148A NO158016B NO 158016 B NO158016 B NO 158016B NO 824148 A NO824148 A NO 824148A NO 824148 A NO824148 A NO 824148A NO 158016 B NO158016 B NO 158016B
- Authority
- NO
- Norway
- Prior art keywords
- dichlorophenoxy
- acid
- ethyl
- diazacyclopent
- alkyl ester
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title claims description 4
- -1 1- (2,6-DICHLORO-PHENOXY) -ETHYL Chemical class 0.000 title description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 8
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 7
- KSMAGQUYOIHWFS-UHFFFAOYSA-N lofexidine Chemical compound N=1CCNC=1C(C)OC1=C(Cl)C=CC=C1Cl KSMAGQUYOIHWFS-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- HOLHYSJJBXSLMV-UHFFFAOYSA-N 2,6-dichlorophenol Chemical compound OC1=C(Cl)C=CC=C1Cl HOLHYSJJBXSLMV-UHFFFAOYSA-N 0.000 claims description 4
- JTSKVVDMNKQPAO-UHFFFAOYSA-N 2-(2,6-dichlorophenoxy)propanoic acid Chemical compound OC(=O)C(C)OC1=C(Cl)C=CC=C1Cl JTSKVVDMNKQPAO-UHFFFAOYSA-N 0.000 claims description 4
- IYGPXILYSHJRMS-UHFFFAOYSA-N n-(2-aminoethyl)-2-(2,6-dichlorophenoxy)propanamide Chemical compound NCCNC(=O)C(C)OC1=C(Cl)C=CC=C1Cl IYGPXILYSHJRMS-UHFFFAOYSA-N 0.000 claims description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 4
- 230000003197 catalytic effect Effects 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- GAWAYYRQGQZKCR-UWTATZPHSA-N (2r)-2-chloropropanoic acid Chemical compound C[C@@H](Cl)C(O)=O GAWAYYRQGQZKCR-UWTATZPHSA-N 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- UKCDLIBIFNZMCQ-UHFFFAOYSA-N ethyl 2-(2,6-dichlorophenoxy)propanoate Chemical class CCOC(=O)C(C)OC1=C(Cl)C=CC=C1Cl UKCDLIBIFNZMCQ-UHFFFAOYSA-N 0.000 description 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000015572 biosynthetic process Effects 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
- JEAVBVKAYUCPAQ-UHFFFAOYSA-N ethyl 2-chloropropanoate Chemical compound CCOC(=O)C(C)Cl JEAVBVKAYUCPAQ-UHFFFAOYSA-N 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000004531 blood pressure lowering effect Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000000694 effects Effects 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
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 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
- 206010020772 Hypertension Diseases 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- 150000007513 acids Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 235000013985 cinnamic acid Nutrition 0.000 description 1
- 229930016911 cinnamic acid Natural products 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000006266 etherification reaction Methods 0.000 description 1
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical class C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- BDAWXSQJJCIFIK-UHFFFAOYSA-N potassium methoxide Chemical compound [K+].[O-]C BDAWXSQJJCIFIK-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- 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
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D233/22—Radicals substituted by oxygen atoms
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Cardiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Photoreceptors In Electrophotography (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstil-
ling av (-)-2-[l-(2,6-diklorfenoksy)-etyl]-l,3-diazacyklo-pent-2-en med formel I
<*> = assymetrisentrum
og denne fremgangsmåte karakteriseres ved at en (-)-2-hydroksypropionsyre Cj^alkylester omsettes med et overskudd av tionylklorid i nærvær av katalytiske mengder dimetylforma-
mid, den resulterende (+)-2-klor-propionsyre-C^_4-alkylester omsettes med minst ekvimolare mengder 2,6-diklorfenol i et organisk oppløsningsmiddel i nærvær av en base ved en temperatur innen området 60 - 150, den resulterende (-)-2-(2,6-diklorfenoksy)propionsyre-C^_4-alkylester på kjent måte omsettes med et stort overskudd av etylendiamin ved romtempe-
ratur, (-)-2-(2,6-diklorfenoksy)-propionsyre N-(2-aminoetyl)-
amid på kjent måte dehydratiseres med et titantetraklorid/- tetrahydrofurankompleks i et inert oppløsningsmiddel i nærvær av 4-dimetylamino pyridin ved en temperatur innen området 0-
30°C.
Fremstillingsmåter for racematet (+)-2-[l-(2,6-diklorfenok-sy )-etyl]-1,3-diazacyklopent-2-en, hvilket er kjent som antihypertonikum, finnes i DE-OS 16.95.555 og DE-OS 19.35.479
samt i DE-PS 17.95.843.
Selv om det var kjent at 2-[1-(2,6-diklorfenoksy)-etyl]-1,3-diazacyklopent-2-en på grunn av det asymmetrisk substituerte karbonatom kan foreligge i to optisk aktive enantiomere former, er en separering henholdsvis fremstilling av optisk aktive venstre- henholdsvis høyredreiende enantiomerer ennå ikke gjennomført.
Separering av den venstredreiende enantiomer for oppklaring av sammenhengen mellom optisk aktivitet og biologisk virksomhet er lykkes ved hjelp av den venstredreiende dibenzoylvin-syre.
De farmakologiske undersøkelser ga meget overraskende at kun den venstredreiende enantiomer viste en sterkt utpreget og langvarig blodtrykksenkende virkning mens den høyredreiende enantiomer i denne modell praktisk talt ikke viste noen virkning.
Også i tilknyttede sammenligninger av den farmakologiske virksomhet for den venstredreiende enantiomer med racematet viste det seg at den halve mengde av den venstredreiende enantiomer var nok til å oppnå en blodtrykkssenkning av bestemt virkningsdybde og virkningsvarighet.
Syntesen av den optisk aktive forbindelse karakteriseres ved at man går ut fra optisk aktive utgangsstoffer. Således blir f. eks. en (-)-2-hydroksypropionsyre-C^-4-alkylester omsatt med overskytende tionylklorid i nærvær av katalytiske mengder av dimetylformamid under konfigurasjonsomdreining til (+)-2-klorpropionsyre-C^_4-alkylester. Den derpå følgende foret-ring med 2,6-diklorfenol skjedde under fornyet konfigurasjonsomdreining i egnede organiske oppløsningsmidler, f. eks. acetonitril, butanon, dimetylformamid i nærvær av hjelpebaser slik som f. eks. natriumhydrid, alkalimetylat, alkalietylat eller 1,4-diazabicyklo-(2,2,2)-oktan i temperaturområdet fra 60 til 150^ og fortrinnsvis ved 80°C til C1_4-alkylesteren av (-)-2-(2,6-diklorfenoksy)-propionsyre, som ved siden av sine funksjonelle syrederivater anvendes som utgangsstoff for syntese av 1,3-diazacyklopenten-derivater. Derved kan omsetningen gjennomføres med etylendiamin selv eller med et reaktivt N-derivat av etylendiamin eller med ammoniakk henholdsvis med ammoniakkavgivende midler og med forbindelser som kan overføres til etylendiamin ved behandling med ammoniakk.
Som funksjonelle syrederivater kan anvendes C^_4-alkylestere, syrehalogenider, amider, tiamider, amidiner, imidsyreestere eller nitrilet av 2-(2,6-diklorfenoksy)-propionsyre.
I foreliggende tilfelle omsettes (-)-2-(2,6-diklorfenoksy)-propionsyreetylestere med stort overskudd av 1,2-diaminetan ved romtemperatur til (-)-2-(2,6-diklorfenoksy )-propionsyre-N-(2-aminoetyl)-amid som igjen dehydratiseres og cykliseres med et titantetraklorid/tetrahydrofurankompleks i kloroform i nærvær av 4-dimetylaminopyridin ved 0 - 30°C til (-)-2-[l-(2,6-diklorfenoksy)-etyl]-1,3-diazacyklopent-2-en.
Den etterfølgende overføring av den venstredreiende base til et fysiologisk akseptabelt syreaddisjonssalt skjer med en egnet anorganisk eller organisk syre i eh lavere alkohol. Således oppnår man fra (-)-basen f. eks. med propanol-2/hydrogenklorid forbindelsen (-)-2-[l-(2,6-diklorfenoksy)-etyl]-1,3-diazacyklopenten-2-hydroklorid.
Fra den frie base av forbindelsen kan man fremstille farma-søytisk akseptable syreaddisjonssalter ved behandling med egnede syrer i henhold til vanlige metoder. For en slik omdanning kommer i betraktning uorganiske syrer som bromhyd-rogensyre, svovelsyre eller fosforsyre, eller organiske syrer som f. eks. eddiksyre, glykolsyre, ravsyre, fumarsyre, eplesyre, vinsyre, sitronsyre, benzosyre eller kanelsyre.
Forbindelsen og dennes farmasøytisk akseptable syreaddisjonssalter oppviser verdifulle farmakologiske egenskaper og spesielt en sterk bl.odtrykkssenkende virkning med lang virkningsvarighet og få bivirkninger. Reduksjonen av den perifere motstand er ønskelig for avlastning av hjertet ved høyt blodtrykk og dette gjør forbindelsen meget egnet for behandling av kretsløpsforstyrrelser.
Fremstillingen av forbindelsene skal beskrives nærmere under henvisning til de ledsagende eksempler. De angitte smelte-punkter er målt med et Buchi 510-smeltepunktbestemmelsesappa-rat og er angitt i °C og ikke korrigert.
Eksempel 1
Syntese av (-)-2-[1-(2,6-diklorfenoksy)-etyl]-1,3-diazacyklopenten-( 2)- hydroklorid
(+)- 2- klorpropionsyreetylester
250 g (tilsvarende 2,119 mol) (-)-2-hydroksypropionsyreetyl-ester [cx]§° = 11,0'C (ufortynnet) kloreres med 264,0 g (tilsvarende 2,218 mol) tionylklorid i nærvær av 1,5 ml dimetylformamid ved koking. Man oppnår 93,0 g ( +)-2-klorpropionsyreetylester C5HgC102 [136,6], Kp: 143°C
[a]§° = +19,8°-c (ufortynnet).
(- )- 2-( 2, 6- diklorfenoksy)- propionsyreetylester
65,5 g (tilsvarende 0,402 mol) 2,6-diklorfenol oppvarmes i 300 ml butanon med 38,8 g (tilsvarende 0,542 mol) kaliumme-tylat og 76,0 g (tilsvarende 0,556 mol) ( +)-2-klorpropionsyreetylester i 48 timer under omrøring og tilbakeløp. Etter opparbeiding oppnår man 62,0 g (-)-2-(2 ,6-diklorfenoksy)-propionsyreetylester C11<H>12C1203 [263,1], Kp0(3: 115 - 117°C [a]§° = 37,1°C (ufortynnet).
(- )- 2-( 2 , 6- diklorfenoks. v)- proplonsyre- N-( 2- aminioetyl )- amid
46,0 g (tilsvarende 0,1748 mol) (-)-2-(2,6-diklorfenoksy )-propionsyreetylester omrøres med 212,0 g (tilsvarende 3,527 mol) 1,2-diaminoetan i 6 timer ved romtemperatur og ga etter opparbeiding 38,0 g (-)-2-(2 ,6-diklorfenoksy)-propionsyre-N-(2-aminoetyl )-amid, CHH14CI2N2O2 [277,2] som høyviskøs olje
N-(2-aminoetyl )-amid, C11H14C12N202 [277,2] som høyviskøs olje
[a]g° = -5,8° (c = 1/etanol).
(-)- 2- l" l-( 2. 6- diklorfenoksy)- etyl]- 1. 3- diazacyklopenten-( 2)
58,6 g (tilsvarende 0,3089 mol) titantetraklorid oppløses ved 0°C i en blanding av 700 ml absolutt kloroform og 25 ml tetrahydrofuran og det tilsettes 35,0 g (tilsvarende 0,1263 mol) (-)-2-(2,6-diklorfenoksy)-propionsyre-N-(2-aminoetyl )-amid. Deretter lar man meget langsomt og ved 0°C under omrøring en oppløsning av 74,0 g (tilsvarende 0,6056 mol) 4-dimetylaminopyridin dryppe til og det hele omrøres videre etter ferdig tilsetning ytterligere 36 timer ved romtemperatur. Etter opparbeiding og søylekromatografi ske rensing (kiselgeltørrsøyle, elueringsmiddel: kloroform/tetrahydrofuran 3:1) oppnår man 21,0 g (-)-2-[1-(2,6-diklorfenoksy)-etyl]-l,3-diazacyklopenten-(2) C11<H>12<C>12N20 [259,1], Fp. 126 - 127°C [a]§° - 80,2° (c = 1/etanol). (-)-2-[l-(2,6-diklorfenoksy)etyl]-l,3-diazacyklopenten-2-hydroklorid
10,0 g (-)-2-[l-(2,6-diklorfenoksy)-etyl]-l,3-diazacyklopenten-(2) oppløses i 40 ml propanol-(2) og det tilsettes 40 ml av en mettet oppløsning av hydrogenklorid i propanol-(2). Man oppnår etter tilsvarende opparbeiding 7,8 g (-2)-2-[l-(2 ,6-diklorfenoksy )-etyl]-l , 3-diazacyklopenten-(2 )-hydroklo-rid <C>11H12C12N20.HC1 [295,6], Fp. 229 - 230°C
[a]§° = -33,2° (c = 1/etanol).
Claims (1)
1.
Fremgangsmåte for fremstilling av (-)-2-[l-(2,6-diklorfenok-sy )-etyl]-l,3-diazacyklopent-2-en med formel I
assymetrisentrum
karakterisert ved at en (-)-2-hydroksypro-pionsyre-Ci_4alkylester omsettes med et overskudd av tionylklorid i nærvær av katalytiske mengder dimetylformamid, den resulterende ( +)-2-klor-propionsyre-Ci_4-alkylester omsettes med minst ekvimolare mengder 2,6-diklorfenol i et organisk oppløsningsmiddel i nærvær av en base ved en temperatur innen området 60 - 150, den resulterende (-)-2-(2,6-diklorfenoksy)-propionsyre-Cj_4-alkylester på kjent måte omsettes med et stort overskudd av etylendiamin ved romtemperatur, (-)-2-(2,6-diklorfenoksy)-propionsyre-N-(2-aminoetyl)-amid på kjent måte dehydratiseres med et titantetraklorid/tetrahydrofuran-kompleks i et inert oppløsningsmiddel i nærvær av 4-dimetylamino pyridin ved en temperatur innen området 0 -30'C.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813149009 DE3149009A1 (de) | 1981-12-10 | 1981-12-10 | (-)-2-(1-(2,6-dichlorphenoxy)-ethyl)-1,3-diazacyclopent-2-en, dessen herstellung und seine verwendung in pharmazeutischen praeparaten |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO824148L NO824148L (no) | 1983-06-13 |
| NO158016B true NO158016B (no) | 1988-03-21 |
| NO158016C NO158016C (no) | 1988-06-29 |
Family
ID=6148418
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO824148A NO158016C (no) | 1981-12-10 | 1982-12-09 | Fremgangsmaate for fremstilling av (-)-2-(1-(2,6-diklor-fenoksy)-etyl)-1,3-diazacyklopent-2-en. |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US4518783A (no) |
| EP (1) | EP0081748B1 (no) |
| JP (1) | JPS58105968A (no) |
| AR (1) | AR242192A1 (no) |
| AT (1) | ATE25520T1 (no) |
| AU (1) | AU553892B2 (no) |
| CA (1) | CA1176641A (no) |
| DD (1) | DD205682A5 (no) |
| DE (2) | DE3149009A1 (no) |
| DK (1) | DK548182A (no) |
| ES (1) | ES518033A0 (no) |
| FI (1) | FI73980C (no) |
| GR (1) | GR77767B (no) |
| IE (1) | IE54222B1 (no) |
| NO (1) | NO158016C (no) |
| PT (1) | PT75961B (no) |
| SU (1) | SU1241989A3 (no) |
| YU (1) | YU273682A (no) |
| ZA (1) | ZA828743B (no) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3407509A1 (de) | 1984-03-01 | 1985-09-05 | A. Nattermann & Cie GmbH, 5000 Köln | Neue arzneimittelkombination zur behandlung von bluthochdruck und thromboembolischen erkrankungen |
| US4801617A (en) * | 1987-04-06 | 1989-01-31 | Leclerc Gerard | Iminoimidazolidines useful in lowering intraocular pressure |
| FR2642422A1 (fr) * | 1988-12-22 | 1990-08-03 | Roussel Uclaf | Nouvelles polyamines acylees, leur procede de preparation et leur application comme fongicides |
| EP2334297A1 (en) * | 2008-08-08 | 2011-06-22 | Agean Llc | Lofexidine enantiomers for use as a treatment for cns disease and pathologies and its chiral synthesis |
| US8101779B2 (en) * | 2008-10-06 | 2012-01-24 | University Of Kentucky Research Foundation | Enantioselective synthesis of (+) and (–)-2-[1-(2,6-dichlorophenoxy)-ethyl]-1,3-diazacyclopent-2-ene |
| IT201900009777A1 (it) | 2019-06-21 | 2020-12-21 | Procos Spa | Processo per la sintesi di lofexidina |
| US20230123335A1 (en) | 2020-04-17 | 2023-04-20 | Medichem, S.A. | Process for the synthesis of lofexidine |
| CN111393369B (zh) * | 2020-05-13 | 2022-12-16 | 宁夏大学 | 一种2-己基咪唑的制备方法 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4025639A (en) * | 1967-02-23 | 1977-05-24 | A. Nattermann & Cie Gmbh | Blood pressure lowering in human mammals |
| DE1695555A1 (de) * | 1967-02-23 | 1970-07-16 | Nordmark Werke Gmbh | Neue Aryloxy-isoalkyl-delta2-imidazoline und deren Saeureadditionssalze sowie Verfahren zu ihrer Herstellung |
| US3966757A (en) * | 1967-02-23 | 1976-06-29 | A. Nattermann & Cie Gmbh | Imidazoline derivatives and processes for the production thereof |
| NL7804482A (nl) * | 1977-04-29 | 1978-10-31 | Ciba Geigy | Preparaten ter bestrijding van ectoparasieten. |
-
1981
- 1981-12-10 DE DE19813149009 patent/DE3149009A1/de not_active Withdrawn
-
1982
- 1982-11-25 IE IE2812/82A patent/IE54222B1/en unknown
- 1982-11-26 ZA ZA828743A patent/ZA828743B/xx unknown
- 1982-12-01 AT AT82111098T patent/ATE25520T1/de not_active IP Right Cessation
- 1982-12-01 EP EP82111098A patent/EP0081748B1/de not_active Expired
- 1982-12-01 DE DE8282111098T patent/DE3275466D1/de not_active Expired
- 1982-12-02 GR GR69957A patent/GR77767B/el unknown
- 1982-12-02 AU AU91059/82A patent/AU553892B2/en not_active Ceased
- 1982-12-07 DD DD82245653A patent/DD205682A5/de unknown
- 1982-12-08 FI FI824216A patent/FI73980C/fi not_active IP Right Cessation
- 1982-12-09 JP JP57214751A patent/JPS58105968A/ja active Pending
- 1982-12-09 CA CA000417366A patent/CA1176641A/en not_active Expired
- 1982-12-09 ES ES518033A patent/ES518033A0/es active Granted
- 1982-12-09 PT PT75961A patent/PT75961B/pt unknown
- 1982-12-09 AR AR82291532A patent/AR242192A1/es active
- 1982-12-09 DK DK548182A patent/DK548182A/da not_active Application Discontinuation
- 1982-12-09 SU SU823521885A patent/SU1241989A3/ru active
- 1982-12-09 NO NO824148A patent/NO158016C/no unknown
- 1982-12-10 YU YU02736/82A patent/YU273682A/xx unknown
-
1983
- 1983-05-27 US US06/498,786 patent/US4518783A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| NO158016C (no) | 1988-06-29 |
| NO824148L (no) | 1983-06-13 |
| EP0081748B1 (de) | 1987-02-25 |
| SU1241989A3 (ru) | 1986-06-30 |
| FI824216A0 (fi) | 1982-12-08 |
| DE3275466D1 (en) | 1987-04-02 |
| IE822812L (en) | 1983-06-10 |
| EP0081748A2 (de) | 1983-06-22 |
| US4518783A (en) | 1985-05-21 |
| AR242192A1 (es) | 1993-03-31 |
| DK548182A (da) | 1983-06-11 |
| YU273682A (en) | 1985-04-30 |
| AU9105982A (en) | 1983-06-16 |
| ES8401947A1 (es) | 1984-01-01 |
| PT75961B (en) | 1985-10-04 |
| ATE25520T1 (de) | 1987-03-15 |
| JPS58105968A (ja) | 1983-06-24 |
| GR77767B (no) | 1984-09-25 |
| IE54222B1 (en) | 1989-07-19 |
| FI73980C (fi) | 1987-12-10 |
| EP0081748A3 (en) | 1984-03-07 |
| DE3149009A1 (de) | 1983-06-23 |
| AU553892B2 (en) | 1986-07-31 |
| PT75961A (en) | 1983-01-01 |
| CA1176641A (en) | 1984-10-23 |
| DD205682A5 (de) | 1984-01-04 |
| ES518033A0 (es) | 1984-01-01 |
| ZA828743B (en) | 1983-09-28 |
| FI73980B (fi) | 1987-08-31 |
| FI824216L (fi) | 1983-06-11 |
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