NO165918B - PROCEDURE FOR THE PREPARATION OF A BENZAMIDE DERIVATIVE AND BENZAMID INTERMEDIATE PRODUCT. - Google Patents
PROCEDURE FOR THE PREPARATION OF A BENZAMIDE DERIVATIVE AND BENZAMID INTERMEDIATE PRODUCT. Download PDFInfo
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- NO165918B NO165918B NO850225A NO850225A NO165918B NO 165918 B NO165918 B NO 165918B NO 850225 A NO850225 A NO 850225A NO 850225 A NO850225 A NO 850225A NO 165918 B NO165918 B NO 165918B
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- Norway
- Prior art keywords
- hydroxy
- formula
- benzamide
- compound
- ethyl
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 29
- 238000002360 preparation method Methods 0.000 title claims description 10
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical class NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 title 2
- 239000013067 intermediate product Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 26
- -1 1-phenyl-but-1-en-3-ylidene Chemical group 0.000 claims description 17
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 10
- 238000011065 in-situ storage Methods 0.000 claims description 9
- 238000006243 chemical reaction Methods 0.000 claims description 8
- 238000002955 isolation Methods 0.000 claims description 7
- WOEISFSYHVAQTR-UHFFFAOYSA-N 5-(2-amino-1-hydroxyethyl)-2-hydroxybenzamide Chemical compound NCC(O)C1=CC=C(O)C(C(N)=O)=C1 WOEISFSYHVAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- SGUAFYQXFOLMHL-UHFFFAOYSA-N 2-hydroxy-5-{1-hydroxy-2-[(4-phenylbutan-2-yl)amino]ethyl}benzamide Chemical compound C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 SGUAFYQXFOLMHL-UHFFFAOYSA-N 0.000 claims description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 5
- BWHOZHOGCMHOBV-UHFFFAOYSA-N benzylideneacetone Chemical compound CC(=O)C=CC1=CC=CC=C1 BWHOZHOGCMHOBV-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 239000007858 starting material Substances 0.000 claims description 5
- DNLPQXRWAKCKPX-UHFFFAOYSA-N 2-carbamoyl-4-[2-(dibenzylazaniumyl)acetyl]phenolate Chemical compound C1=C(O)C(C(=O)N)=CC(C(=O)CN(CC=2C=CC=CC=2)CC=2C=CC=CC=2)=C1 DNLPQXRWAKCKPX-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- 229910052697 platinum Inorganic materials 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- AKGGYBADQZYZPD-UHFFFAOYSA-N benzylacetone Chemical compound CC(=O)CCC1=CC=CC=C1 AKGGYBADQZYZPD-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 125000000468 ketone group Chemical group 0.000 description 3
- 239000012429 reaction media Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- RVLDETSVEUQULS-UHFFFAOYSA-N 5-(2-amino-1-hydroxyethyl)-2-hydroxybenzamide;hydrochloride Chemical compound Cl.NCC(O)C1=CC=C(O)C(C(N)=O)=C1 RVLDETSVEUQULS-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WQVZLXWQESQGIF-UHFFFAOYSA-N Labetalol hydrochloride Chemical compound Cl.C=1C=C(O)C(C(N)=O)=CC=1C(O)CNC(C)CCC1=CC=CC=C1 WQVZLXWQESQGIF-UHFFFAOYSA-N 0.000 description 2
- 239000002262 Schiff base Substances 0.000 description 2
- 150000004753 Schiff bases Chemical class 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 229960004132 diethyl ether Drugs 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
- 229910052759 nickel Inorganic materials 0.000 description 2
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 2
- 229910003446 platinum oxide Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- VXWSXLSUWGZOHD-UHFFFAOYSA-N 5-(2-bromoacetyl)-2-hydroxybenzamide Chemical compound NC(=O)C1=CC(C(=O)CBr)=CC=C1O VXWSXLSUWGZOHD-UHFFFAOYSA-N 0.000 description 1
- LWAQTCWTCCNHJR-UHFFFAOYSA-N 5-acetyl-2-hydroxybenzamide Chemical compound CC(=O)C1=CC=C(O)C(C(N)=O)=C1 LWAQTCWTCCNHJR-UHFFFAOYSA-N 0.000 description 1
- XNBPIZTUCVHIFW-UHFFFAOYSA-N CC(=O)C=CC1=CC=CC=C1.CC(=O)C=CC1=CC=CC=C1 Chemical compound CC(=O)C=CC1=CC=CC=C1.CC(=O)C=CC1=CC=CC=C1 XNBPIZTUCVHIFW-UHFFFAOYSA-N 0.000 description 1
- BWLUMTFWVZZZND-UHFFFAOYSA-N Dibenzylamine Chemical compound C=1C=CC=CC=1CNCC1=CC=CC=C1 BWLUMTFWVZZZND-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 150000003936 benzamides Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- MPMBRWOOISTHJV-UHFFFAOYSA-N but-1-enylbenzene Chemical compound CCC=CC1=CC=CC=C1 MPMBRWOOISTHJV-UHFFFAOYSA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- JXYZHMPRERWTPM-UHFFFAOYSA-N hydron;morpholine;chloride Chemical compound Cl.C1COCCN1 JXYZHMPRERWTPM-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- ZASBYHZJHQFLGN-UHFFFAOYSA-N n-benzyl-4-phenylbutan-2-amine Chemical compound C=1C=CC=CC=1CNC(C)CCC1=CC=CC=C1 ZASBYHZJHQFLGN-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- BWHOZHOGCMHOBV-BQYQJAHWSA-N trans-benzylideneacetone Chemical compound CC(=O)\C=C\C1=CC=CC=C1 BWHOZHOGCMHOBV-BQYQJAHWSA-N 0.000 description 1
- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse angår en fremgangsmåte for fremstilling av et benzamidderivat. Nærmere bestemt angår oppfinnelsen en ny og forbedret fremgangsmåte for fremstilling av 2-hydroxy-5-£l-hydroxy-2-[(l-methyl-3-fenylpropyl)-aitiino]-ethyl}-benzamid og farmasøytisk akseptable syreaddisjonssalter derav. The present invention relates to a method for producing a benzamide derivative. More specifically, the invention relates to a new and improved process for the production of 2-hydroxy-5-£1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide and pharmaceutically acceptable acid addition salts thereof.
Det er kjent at 2-hydroxy-5-{.l-hydroxy-2-[ (l-methyl-S-fenylpropyl)-amino]-ethyl)-benzamid er et nyttig og vidt anvendt a- og ^-blokkerende hypotensivt middel. It is known that 2-hydroxy-5-{.1-hydroxy-2-[ (1-methyl-S-phenylpropyl)-amino]-ethyl)-benzamide is a useful and widely used α- and β-blocking hypotensive agent .
Innen teknikkens stand er det beskrevet en rekke prose-dyrer for fremstilling av 2-hydroxy-5-[l-hydroxy-2-[(1-methyl-3-fenylpropyl)-amino]-ethyl}-benzamid. Ifølge DOS 2 032 642 bromeres 2-hydroxy-5-acetylbenzamid, det således erholdte iu-bromacetyladerivat omsettes med N-benzyl-N-(l-methyl-3-fenylpropyl)-amin, og ketogruppen i 2-hydroxy-5-[ 2-[N-benzyl-N-(l-methyl-3-fenylpropyl)-amino]-acetyl}-benzamid reduseres ved katalytisk hydrogenering mens den be-skyttende N-benzylgruppe splittes under dannelse av 2-hydroxy-5-{l-hydroxy-2-[(l-methyl-3-fenylpropyl)-amino]-ethyl}-benzamid. Within the state of the art, a number of procedures for the production of 2-hydroxy-5-[1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide have been described. According to DOS 2 032 642, 2-hydroxy-5-acetylbenzamide is brominated, the iu-bromoacetyl derivative thus obtained is reacted with N-benzyl-N-(1-methyl-3-phenylpropyl)-amine, and the keto group in 2-hydroxy-5-[ 2-[N-benzyl-N-(1-methyl-3-phenylpropyl)-amino]-acetyl}-benzamide is reduced by catalytic hydrogenation while the protecting N-benzyl group is split to form 2-hydroxy-5-{l -hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide.
Ulempen ved denne fremgangsmåte er at sluttproduktet erholdes ved hjelp av en syntese som omfatter mange trinn og i lave utbytter. Ennvidere kan N-benzyl-N-(l-methyl-S-fenyl-propyl )-amin-komponenten bare fremstilles ved en flertrinns-syntese på en komplisert måte. The disadvantage of this method is that the final product is obtained by means of a synthesis which comprises many steps and in low yields. Furthermore, the N-benzyl-N-(1-methyl-S-phenyl-propyl)-amine component can only be prepared by a multi-step synthesis in a complicated manner.
Ifølge en annen fremgangsmåte beskrevet i DOS 2 032 64 2, omsettes 2-hydroxy-5-(bromacetyl)-benzamid med N,N-dibenzyl-amin, og det erholdte 2-hydroxy-5-(N,N-dibenzylglycyl)-benzamid av formel omsettes med 1-fenyl-3-butanon under reduserende betingelser. De oppnådde utbytter er middels. En ytterligere ulempe ved denne metode består i det faktum at 1-fenyl-3-butanon ikke er tilgjengelig i industriell målestokk, og innen teknikkens stand er det ikke beskrevet noen industriell fremstillings-prosess for angitte forbindelse. According to another method described in DOS 2 032 64 2, 2-hydroxy-5-(bromoacetyl)-benzamide is reacted with N,N-dibenzyl-amine, and the obtained 2-hydroxy-5-(N,N-dibenzylglycyl)- benzamide of formula is reacted with 1-phenyl-3-butanone under reducing conditions. The yields obtained are medium. A further disadvantage of this method consists in the fact that 1-phenyl-3-butanone is not available on an industrial scale, and within the state of the art no industrial production process for the specified compound has been described.
Ifølge en ytterligere metode beskrevet i angitte According to a further method described in specified
DOS, omsettes 5-(2-amino-l-hydroxyethyl)-salicylamid med 1-fenyl-3-butanon i ethanolisk løsning under reduserende betingelser under dannelse av den ønskede forbindelse 2-hydroxy-5-$l-hydroxy-2-[(l-methyl-3-fenylpropyl)-amino]-ethyl} - benzamid. DOS, 5-(2-amino-1-hydroxyethyl)-salicylamide is reacted with 1-phenyl-3-butanone in ethanolic solution under reducing conditions to form the desired compound 2-hydroxy-5-$1-hydroxy-2-[ (1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide.
I det tilsvarende eksempel er imidlertid intet utbytte angitt. En ulempe ved denne metode er som tidligere angitt, at 1-fenyl-3-butanon-utgangsmaterialet ikke er tilgjengelig i industriell målestokk. In the corresponding example, however, no dividend is specified. A disadvantage of this method is, as previously indicated, that the 1-phenyl-3-butanone starting material is not available on an industrial scale.
I belgisk patentskrift 840 779 og DOS 2 616 403 be-skrives en fremgangsmåte for fremstilling og separering av diastereoisomerer av 2-hydroxy-5-Ll-hydroxy-2-f(l-methyl-3-fenylpropyl)-amino]-ethyl}-benzamid. I de der beskrevne metoder vil som et resultat av dannelsen av det chirale senter antallet av reaksjonstrinn øke, og det totale utbytte ved syntesen er relativt lavt. In Belgian patent document 840 779 and DOS 2 616 403, a method for the preparation and separation of diastereoisomers of 2-hydroxy-5-L1-hydroxy-2-f(1-methyl-3-phenylpropyl)-amino]-ethyl} is described -benzamide. In the methods described there, as a result of the formation of the chiral center, the number of reaction steps increases, and the total yield of the synthesis is relatively low.
Ifølge de generelle formler angitt i ungarsk patentskrift 165 291, kan 2-hydroxy-5-{l-hydroxy-2-[(l-methyl-3-fenylpropyl)-amino]-ethyl]-benzamid fremstilles ved kondenser-ing av 2-hydroxy-5-glyoxylylbenzosyreester med l-fenyl-3-butylamin, hvoretter den således erholdte Schiff-base underkastes katalytisk hydrogenering. I patentskriftet er det imidlertid ikke angitt noe eksempel for fremstilling av 2-hydroxy-5-(l-hydroxy-2-[(l-methyl-3-fenylpropyl)-amino]-ethyl}-benzamid. According to the general formulas stated in Hungarian patent document 165 291, 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl]-benzamide can be prepared by condensing 2 -hydroxy-5-glyoxylylbenzoic acid ester with l-phenyl-3-butylamine, after which the Schiff base thus obtained is subjected to catalytic hydrogenation. In the patent, however, no example is given for the preparation of 2-hydroxy-5-(1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide.
Et mål med oppfinnelsen er å utvikle en fremgangsmåte for fremstilling av 2-hydroxy-5-{l-hydroxy-2-[(l-methyl-3-fenylpropyl)-amino]-ethyl} -benzamid som eliminerer de oven-for angitte ulemper ved de kjente metoder som gir høyere utbytter, er lett gjennomførbar i industriell målestokk og som anvender lett tilgjengelige utgangsmaterialer. An aim of the invention is to develop a method for the production of 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenylpropyl)-amino]-ethyl}-benzamide which eliminates the above-mentioned disadvantages of the known methods which give higher yields, are easily feasible on an industrial scale and which use readily available starting materials.
Oppfinnelsen angår således en fremgangsmåte for fremstilling av 2-hydroxy-5- {l-hydroxy-2- [( l-methyl-3-fenyl-propyl)-amino}-ethyl^ -benzamid av formel The invention thus relates to a process for the production of 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenyl-propyl)-amino}-ethyl^-benzamide of the formula
og farmasøytisk akseptable syreaddisjonssalter derav, hvilken fremgangsmåte er kjennetegnet ved at 2-hydroxy-5--£l-hydroxy-2-[(1-fenyl-but-l-en-3-yliden)-imino]-ethyl}-benzamid av formel and pharmaceutically acceptable acid addition salts thereof, which method is characterized in that 2-hydroxy-5--£1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl}-benzamide of formula
hydrogeneres i nærvær av en katalysator i et inert organisk løsningsmiddel, og, om ønsket, at forbindelsen av formel I omdannes til et farmasøytisk akseptabelt syreaddisjonsselt. is hydrogenated in the presence of a catalyst in an inert organic solvent, and, if desired, that the compound of formula I is converted to a pharmaceutically acceptable acid addition salt.
Reduksjonen av Schiff-basen av fprmel V kan utføres ved katalytisk hydrogenering. Som katalysator anvendes fortrinnsvis palladium, platina, nikkel eller en Adams-katalysator. Katalysatoren kan også tilføres på en bærer (f.eks. benkull, bariumsulfat). Hydrogeneringen kan utføres ved en temperatur mellom 10 og 40°C, fortrinnsvis ved en temperatur på 20-30°C, og under et trykk på 1-10 atm., fortrinnsvis 2-4 atm. Man kan særlig fordelaktig arbeide ved 25°C og under et trykk på 3 atm. Reduksjonen utføres i et inert organisk løsningsmiddel. Som reaksjonsmedium anvendes fortrinnsvis en ether (f.eks. diethylether, dioxan eller tetrahydrofuran) eller en alkohol (f.eks. methanol eller ethanol), i særdeleshet tetrahydrofuran. Under reaksjonsforløpet for-brukes to ekvivalenter hydrogen, og både azomethinbindingen og carbon-carbon-dobbeltbindingen mettes. Reaksjonen kan ut-føres i nærvær av en liten mengde av en organisk syre (f.eks. iseddik). De oppnådde utbytter er praktisk talt teoretisk e. The reduction of the Schiff base of formula V can be carried out by catalytic hydrogenation. The catalyst used is preferably palladium, platinum, nickel or an Adams catalyst. The catalyst can also be supplied on a carrier (e.g. bone charcoal, barium sulphate). The hydrogenation can be carried out at a temperature between 10 and 40°C, preferably at a temperature of 20-30°C, and under a pressure of 1-10 atm., preferably 2-4 atm. It is particularly advantageous to work at 25°C and under a pressure of 3 atm. The reduction is carried out in an inert organic solvent. An ether (e.g. diethyl ether, dioxane or tetrahydrofuran) or an alcohol (e.g. methanol or ethanol), in particular tetrahydrofuran, is preferably used as the reaction medium. During the course of the reaction, two equivalents of hydrogen are consumed, and both the azomethine bond and the carbon-carbon double bond are saturated. The reaction can be carried out in the presence of a small amount of an organic acid (e.g. glacial acetic acid). The yields obtained are practically theoretical e.
Reaksjonsblandingen kan opparbeides på kjent måte. Katalysatoren filtreres fortrinnsvis fra, og filtratet for-dampes. Hydrokloridet kan isoleres ved tilsetning av vann-fritt ethanolisk hydrogenklorid eller en blanding av konsen-trert saltsyre og ethanol til det hydrogenerte filtrat. The reaction mixture can be worked up in a known manner. The catalyst is preferably filtered off, and the filtrate is evaporated. The hydrochloride can be isolated by adding anhydrous ethanolic hydrogen chloride or a mixture of concentrated hydrochloric acid and ethanol to the hydrogenated filtrate.
Utgangsmaterialet av formel V er en ny forbindelse og kan fremstilles ved omsetning av 2-hydroxy-5-(l-hydroxy-2-aminoethyl)-benzamid av formel The starting material of formula V is a new compound and can be prepared by reacting 2-hydroxy-5-(1-hydroxy-2-aminoethyl)-benzamide of formula
med 1-fenyl-but-l-en-3-on av formel with 1-phenyl-but-1-en-3-one of formula
Reaksjonen kan utføres i et inert, organisk løsningsmiddel. Som reaksjonsmedium anvendes fortrinnsvis en ether (f.eks. diethylether, dioxan eller tetrahydrofuran), alkohol (f.eks. methanol eller ethanol) eller et aromatisk hydrocarbon (f.eks. benzen, toluen eller xylen), i særdeleshet tetrahydrofuran. Reaksjonen kan utføres ved en temperatur mellom 25 og 100°C, fortrinnsvis ved en temperatur på rundt 40°C. Reaksjonen kan eventuelt utføres i nærvær av en base (f.eks. triethylamin eller morfolin). The reaction can be carried out in an inert, organic solvent. An ether (e.g. diethylether, dioxane or tetrahydrofuran), alcohol (e.g. methanol or ethanol) or an aromatic hydrocarbon (e.g. benzene, toluene or xylene), in particular tetrahydrofuran, is preferably used as the reaction medium. The reaction can be carried out at a temperature between 25 and 100°C, preferably at a temperature of around 40°C. The reaction can optionally be carried out in the presence of a base (eg triethylamine or morpholine).
Den således erholdte forbindelse av formel V kan enten isoleres eller underkastes katalytisk hydrogenering in situ uten isolering. The thus obtained compound of formula V can either be isolated or subjected to catalytic hydrogenation in situ without isolation.
Ifølge en utførelsesform av fremgangsmåten ifølge oppfinnelsen kan forbindelsen av formel II fremstilt ved katalytisk hydrogenering av forbindelsen av formel According to one embodiment of the method according to the invention, the compound of formula II can be prepared by catalytic hydrogenation of the compound of formula
anvendes. Fortrinnsvis underkastes en forbindelse av formel VI katalytisk hydrogenering, den således dannede forbindelse av formel II omsettes in situ med forbindelsen av formel III, og den således dannede forbindelse av formel V hydrogeneres uten isolering. are used. Preferably, a compound of formula VI is subjected to catalytic hydrogenation, the compound of formula II thus formed is reacted in situ with the compound of formula III, and the compound of formula V thus formed is hydrogenated without isolation.
Ifølge en ytterligere utførelsesform av fremgangsmåten ifølge oppfinnelsen anvendes forbindelsen av formel II fremstilt ved katalytisk hydrogenering av forbindelsen av formel IV. Forbindelsen av formel IV underkastes katalytisk hydrogenering, den således dannede forbindelse av formel II omsettes in situ med en forbindelse av formel III, og den dannede forbindelse av formel V hydrogeneres uten isolering. According to a further embodiment of the method according to the invention, the compound of formula II prepared by catalytic hydrogenation of the compound of formula IV is used. The compound of formula IV is subjected to catalytic hydrogenation, the compound of formula II thus formed is reacted in situ with a compound of formula III, and the compound of formula V formed is hydrogenated without isolation.
De to sistnevnte utførelsesformer av fremgangsmåten ifølge oppfinnelsen kan fortrinnsvis utføres ved en forhøyet temperatur, fortrinnsvis ved 50-70°C og et trykk på mellom 1 og 100 atm, fortrinnsvis under et trykk på rundt 50 atm. Reaksjonen kan utføres i et inert organisk løsningsmiddel. Som reaksjonsmedium kan fortrinnsvis anvendes en alkohol (f.eks. methanol eller ethanol). Reaksjonsblandingen kan også inneholde en syre (f.eks. eddiksyre). Som katalysator kan anvendes palladium, platina, nikkel eller Adams-katalysator. Katalysatoren kan tilføres på en bærer, f.eks. benkull, bariumsulfat etc, om ønsket. The two latter embodiments of the method according to the invention can preferably be carried out at an elevated temperature, preferably at 50-70°C and a pressure of between 1 and 100 atm, preferably under a pressure of around 50 atm. The reaction can be carried out in an inert organic solvent. An alcohol (e.g. methanol or ethanol) can preferably be used as the reaction medium. The reaction mixture may also contain an acid (e.g. acetic acid). Palladium, platinum, nickel or Adams catalyst can be used as a catalyst. The catalyst can be supplied on a carrier, e.g. bone charcoal, barium sulphate etc, if desired.
Hovedfordelen ved fremgangsmåten ifølge oppfinnelsen er at utgangsmaterialene anvendt for fremstilling av forbindelsen av formel V, kan fremstilles fra materialer (f.eks. benzalaceton) som er lett tilgjengelig i industriell målestokk, prosessen er lett gjennomførbar og økonomisk i industriell målestokk, og høye utbytter oppnås. The main advantage of the method according to the invention is that the starting materials used for the preparation of the compound of formula V can be produced from materials (e.g. benzalacetone) which are readily available on an industrial scale, the process is easily feasible and economical on an industrial scale, and high yields are achieved .
Uten å begrense oppfinnelsens ramme ved teoretiske be-traktninger antas det at dette skyldes det faktum at på grunn av konjugasjon er ketogruppen av 1-fenyl-but-l-en-3-on (benzalaceton) anvendt ved fremgangsmåten ifølge oppfinnelsen, mer reaktiv enn ketogruppen av 1-fenyl-butan-3-on anvendt ved fremgangsmåten beskrevet i DOS 2 032 64 2. Av denne grunn reagerer forbindelsen av formel III med 2-hydroxy-5-(1-hydroxy-2-aminoethyl)-benzamid av formel II under dannelse av det tilsvarende 2-hydroxy-5-^l-hydroxy-2-[(1-fenyl-but-l-en-3-yliden)-imino]-ethyl]-benzamid meget lettere enn det tilsvarende mellomprodukt som dannes ved fremgangsmåten beskrevet i DOS 2 032 642, nemlig 2-hydroxy-5-{_l-hydroxy-2-[ (1-f enyl-but-3-yliden)-imino]-ethyl} -benzamid eller 2-hydroxy-5-{l-keto-2-[(1-fenyl-but-3-yliden)-imino]-ethyl} -benzamid. Without limiting the scope of the invention by theoretical considerations, it is assumed that this is due to the fact that, due to conjugation, the keto group of 1-phenyl-but-1-en-3-one (benzalacetone) used in the method according to the invention is more reactive than the keto group of 1-phenyl-butan-3-one used in the method described in DOS 2 032 64 2. For this reason, the compound of formula III reacts with 2-hydroxy-5-(1-hydroxy-2-aminoethyl)-benzamide of formula II while forming the corresponding 2-hydroxy-5-^1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl]-benzamide much more easily than the corresponding intermediate which is formed by the method described in DOS 2 032 642, namely 2-hydroxy-5-{_1-hydroxy-2-[(1-phenyl-but-3-ylidene)-imino]-ethyl}-benzamide or 2-hydroxy- 5-{1-keto-2-[(1-phenyl-but-3-ylidene)-imino]-ethyl}-benzamide.
Oppfinnelsen illustreres ytterligere i de etterfølgende eksempler. The invention is further illustrated in the following examples.
Eksempel 1 Example 1
Fremstilling av 2-hydroxy-5-{l-hydroxy-2-[(1-fenyl-but-1-e n- 3- yliden)- amino]- ethyl) - benzamid Preparation of 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-ene n-3-ylidene)-amino]-ethyl)-benzamide
2,30 g (10 millimol) 2-hydroxy-5-(l-hydroxy-2-amino-ethyl)-benzamid-hydroklorid og 1,46 g (10 millimol) 1-fenyl-but-l-en-3-on ble blandet med 10 ml tetrahydrofuran, hvorpå 2.30 g (10 millimoles) of 2-hydroxy-5-(1-hydroxy-2-amino-ethyl)-benzamide hydrochloride and 1.46 g (10 millimoles) of 1-phenyl-but-l-ene-3- was mixed with 10 ml of tetrahydrofuran, whereupon
det under ytterligere omrøring og isavkjøling ble dråpevis tilsatt 1,20 ml triethylamin ved en temperatur på 10-15°C. with further stirring and ice cooling, 1.20 ml of triethylamine was added dropwise at a temperature of 10-15°C.
Når tilsetningen var fullført, ble reaksjonsblandingen omrørt ved romtemperatur i ytterligere 5 timer, og det utfelte triethylamin-hydroklorid ble filtrert fra. Fra filtratet ble 2- hydroxy-5-{l-hydroxy-2-[(1-fenyl-but-l-en-3-yliden)-imino]-ethyl}-benzamid isolert ved kolonnekromatografi på silicagel. Det ble således erholdt 1,56 g av den ønskede forbindelse, utbytte 48%, smp. 142-146°C. When the addition was complete, the reaction mixture was stirred at room temperature for an additional 5 hours, and the precipitated triethylamine hydrochloride was filtered off. From the filtrate, 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl}-benzamide was isolated by column chromatography on silica gel. 1.56 g of the desired compound were thus obtained, yield 48%, m.p. 142-146°C.
Eksempel 2 Example 2
Fremstilling av 2-hydroxy-5-{l-hydroxy-2-[(1-fenyl-but-l-en-3- yliden)- imino]- ethyl} - benzamid Preparation of 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl}-benzamide
2,30 g (10 millimol) 2-hydroxy-5-(l-hydroxy-2-amino-ethyl)-benzamid-hydroklorid og 1,46 g (10 millimol) 1-fenyl-but-l-en-3-on ble blandet med 10 ml tetrahydrofuran, hvorpå det under omrøring og isavkjøling ble dråpevis tilsatt 4 ml morfolin ved en temperatur på 10-15°C. Reaksjonsblandingen ble omrørt ved romtemperatur i ytterligere 5 timer, det utfelte morfolin-hydroklorid ble filtrert fra, og filtratet ble oppvarmet til kokning i 3 timer. Fra filtratet ble den ønskede forbindelse isolert ved kolonnekromatografi på silicagel. Det ble således erholdt 2,05 g av den ønskede forbindelse, utbytte 63%, smp.: 142-145°C. 2.30 g (10 millimoles) of 2-hydroxy-5-(1-hydroxy-2-amino-ethyl)-benzamide hydrochloride and 1.46 g (10 millimoles) of 1-phenyl-but-l-ene-3- was mixed with 10 ml of tetrahydrofuran, after which 4 ml of morpholine was added dropwise at a temperature of 10-15°C while stirring and cooling with ice. The reaction mixture was stirred at room temperature for an additional 5 hours, the precipitated morpholine hydrochloride was filtered off, and the filtrate was heated to boiling for 3 hours. From the filtrate, the desired compound was isolated by column chromatography on silica gel. 2.05 g of the desired compound were thus obtained, yield 63%, mp: 142-145°C.
Eksempel 3 Example 3
Fremstilling av 2-hydroxy-5-{l-hydroxy-2-[(l-methyl-3-fenyl-propyl) - amino]- ethyl}- benzamid- hydroklorid Preparation of 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenyl-propyl)-amino]-ethyl}-benzamide hydrochloride
3,24 g (10 millimol) 2-hydroxy-5-{l-hydroxy-2-[(1-fenyl-but-l-en-3-yliden)-imino]-ethyl}-benzamid fremstilt i henhold til eksempel 1 eller 2, ble oppløst i 25 ml tetrahydrofuran, hvorpå 0,5 g 10% palladium-på-carbonkatalysator ble tilsatt, og blandingen ble hydrogenert ved en temperatur på 25°C under et trykk på 3 atm. Når reduksjonen var avsluttet, ble katalysatoren filtrert fra, og til filtratet ble tilsatt 5 ml ethanol inneholdende 20% saltsyre. De utfelte, hvite krystaller ble filtrert fra og vasket med ethanol. Det ble således erholdt 3,46 g av den ønskede forbindelse, utbytte 95%, 3.24 g (10 millimoles) of 2-hydroxy-5-{1-hydroxy-2-[(1-phenyl-but-1-en-3-ylidene)-imino]-ethyl}-benzamide prepared according to Example 1 or 2, was dissolved in 25 ml of tetrahydrofuran, whereupon 0.5 g of 10% palladium-on-carbon catalyst was added, and the mixture was hydrogenated at a temperature of 25°C under a pressure of 3 atm. When the reduction was finished, the catalyst was filtered off, and 5 ml of ethanol containing 20% hydrochloric acid was added to the filtrate. The precipitated white crystals were filtered off and washed with ethanol. 3.46 g of the desired compound were thus obtained, yield 95%,
smp. 188-189°C. m.p. 188-189°C.
Eksempel 4 Example 4
Fremstilling av 2-hydroxy-5- {l-hydroxy-2-[(l-methyl-3-fenyl-propyl)- amino]- ethyl)- benzamid- hydrolklorid Preparation of 2-hydroxy-5-{1-hydroxy-2-[(1-methyl-3-phenyl-propyl)-amino]-ethyl)-benzamide hydrochloride
Til en løsning av 3,74 g (10 millimol) 2-hydroxy-5-(N,N-dibenzylglycyl)-benzamid, 1,46 g (10 millimol) 1-fenyl-but-l-en-3-on og 50 ml methanol ble tilsatt 1,0 ml iseddik, 1,0 g 10% palladium-på-carbonkatalysator og 0,1 g platinaoxyd (Adams-katalysator). Reaksjonsblandingen ble hydrogenert ved en temperatur på 60°C og under et trykk på 50 atm. Katalysatoren ble filtrert fra, og filtratet ble fordampet til et lite volum. Til residuet ble tilsatt 3 ml propanol mettet med hydrogenklorid og 5 ml ethylacetat. Ved henstand utskiltes krystaller som ble filtrert fra og vasket. Det ble således erholdt 2,62 g av den ønskede forbindelse med utbytte 72%, smp. 187-190°C. To a solution of 3.74 g (10 millimoles) of 2-hydroxy-5-(N,N-dibenzylglycyl)-benzamide, 1.46 g (10 millimoles) of 1-phenyl-but-l-en-3-one and 50 ml of methanol was added to 1.0 ml of glacial acetic acid, 1.0 g of 10% palladium-on-carbon catalyst and 0.1 g of platinum oxide (Adams catalyst). The reaction mixture was hydrogenated at a temperature of 60°C and under a pressure of 50 atm. The catalyst was filtered off and the filtrate was evaporated to a small volume. 3 ml of propanol saturated with hydrogen chloride and 5 ml of ethyl acetate were added to the residue. On standing, crystals were separated which were filtered off and washed. 2.62 g of the desired compound were thus obtained with a yield of 72%, m.p. 187-190°C.
Eksempel 5 Example 5
Fremstilling av 2-hydroxy-5-£l-hydroxy-2-[(l-methyl-3-fenyl-propyl)- amino]- ethyl) - benzamid- hydroklorid Preparation of 2-hydroxy-5-£1-hydroxy-2-[(1-methyl-3-phenyl-propyl)-amino]-ethyl)-benzamide hydrochloride
Til en løsning av 3,76 g (10 millimol) 2-hydroxy-5-[l-hydroxy-2-(dlbenzylamino)-ethyl]-benzamid og 1,46 g To a solution of 3.76 g (10 millimoles) of 2-hydroxy-5-[1-hydroxy-2-(dlbenzylamino)-ethyl]-benzamide and 1.46 g
(10 millimol) 1-fenyl-but-l-en-3-on i 50 ml methanol ble tilsatt 1,0 ml iseddik, 1,0 g av en 10%-ig palladium-oå-carbonkatalysator og 0,1 g platinaoxyd (Adams-katalysa^or), og reaksjonsblandingen ble hydrogenert ved en tempera tu.c på 60°C (10 millimoles) of 1-phenyl-but-1-en-3-one in 50 ml of methanol was added 1.0 ml of glacial acetic acid, 1.0 g of a 10% palladium-o-carbon catalyst and 0.1 g of platinum oxide (Adams catalyst), and the reaction mixture was hydrogenated at a temperature of 60°C
og under et trykk, på 50 atm. Reaks jonsblandingen..jle opp-arbeidet, og produktet ble isolert som beskrevet i eksempel 4. Det ble således erholdt 2,77 g av det ønskede produkt, utbytte 76%, smp. 188-189°C. and under a pressure of 50 atm. The react ion mixture..jle up the work, and the product was isolated as described in example 4. 2.77 g of the desired product were thus obtained, yield 76%, m.p. 188-189°C.
Claims (8)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU23484A HU190867B (en) | 1984-01-20 | 1984-01-20 | Process for preparing 2-hydroxy-5-/1-hydroxy-2-/1-methyl-3-phenyl-propyl/-amino/ethyl/-benzamide and pharmaceutically acceptable salts thereof |
Publications (3)
Publication Number | Publication Date |
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NO850225L NO850225L (en) | 1985-07-22 |
NO165918B true NO165918B (en) | 1991-01-21 |
NO165918C NO165918C (en) | 1991-05-02 |
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Application Number | Title | Priority Date | Filing Date |
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NO850225A NO165918C (en) | 1984-01-20 | 1985-01-18 | PROCEDURE FOR THE PREPARATION OF A BENZAMIDE DERIVATIVE AND BENZAMID INTERMEDIATE PRODUCT. |
Country Status (18)
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JP (1) | JPS60231639A (en) |
AT (1) | AT390612B (en) |
CA (1) | CA1239938A (en) |
CH (1) | CH662810A5 (en) |
CS (1) | CS249536B2 (en) |
DD (1) | DD228245A5 (en) |
DE (1) | DE3501582A1 (en) |
DK (1) | DK26185A (en) |
ES (1) | ES8608481A1 (en) |
FI (1) | FI83635C (en) |
FR (1) | FR2558465B1 (en) |
GB (1) | GB2152931B (en) |
HU (1) | HU190867B (en) |
NL (1) | NL8500119A (en) |
NO (1) | NO165918C (en) |
PT (1) | PT79844B (en) |
SE (1) | SE8500236L (en) |
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GB1247370A (en) * | 1968-12-31 | 1971-09-22 | Allen & Hanburys Ltd | Glyoxals and production thereof |
ZA794872B (en) * | 1978-09-20 | 1980-11-26 | Schering Corp | A phenylalkylaminoethylsalicylamide,its preparation and pharmaceutical compositions containing it |
-
1984
- 1984-01-20 HU HU23484A patent/HU190867B/en not_active IP Right Cessation
- 1984-12-17 CH CH598584A patent/CH662810A5/en not_active IP Right Cessation
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1985
- 1985-01-18 ES ES540121A patent/ES8608481A1/en not_active Expired
- 1985-01-18 NO NO850225A patent/NO165918C/en unknown
- 1985-01-18 DE DE19853501582 patent/DE3501582A1/en not_active Withdrawn
- 1985-01-18 DK DK26185A patent/DK26185A/en not_active Application Discontinuation
- 1985-01-18 AT AT11685A patent/AT390612B/en not_active IP Right Cessation
- 1985-01-18 FI FI850229A patent/FI83635C/en not_active IP Right Cessation
- 1985-01-18 SU SU853837675A patent/SU1521281A3/en active
- 1985-01-18 CA CA000472445A patent/CA1239938A/en not_active Expired
- 1985-01-18 CS CS37785A patent/CS249536B2/en unknown
- 1985-01-18 PT PT7984485A patent/PT79844B/en unknown
- 1985-01-18 GB GB08501246A patent/GB2152931B/en not_active Expired
- 1985-01-18 DD DD27264985A patent/DD228245A5/en not_active IP Right Cessation
- 1985-01-18 NL NL8500119A patent/NL8500119A/en not_active Application Discontinuation
- 1985-01-18 FR FR8500702A patent/FR2558465B1/en not_active Expired
- 1985-01-18 JP JP597885A patent/JPS60231639A/en active Pending
- 1985-06-06 SE SE8500236A patent/SE8500236L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
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JPS60231639A (en) | 1985-11-18 |
CS249536B2 (en) | 1987-03-12 |
SE8500236L (en) | 1985-07-21 |
FI83635B (en) | 1991-04-30 |
FR2558465A1 (en) | 1985-07-26 |
FI850229A0 (en) | 1985-01-18 |
GB2152931B (en) | 1987-03-18 |
ATA11685A (en) | 1989-11-15 |
FR2558465B1 (en) | 1988-08-26 |
AT390612B (en) | 1990-06-11 |
NL8500119A (en) | 1985-08-16 |
PT79844A (en) | 1985-02-01 |
SU1521281A3 (en) | 1989-11-07 |
HUT36779A (en) | 1985-10-28 |
NO165918C (en) | 1991-05-02 |
CH662810A5 (en) | 1987-10-30 |
GB2152931A (en) | 1985-08-14 |
DK26185A (en) | 1985-07-21 |
ES8608481A1 (en) | 1986-07-16 |
DE3501582A1 (en) | 1985-08-01 |
NO850225L (en) | 1985-07-22 |
FI850229L (en) | 1985-07-21 |
CA1239938A (en) | 1988-08-02 |
SE8500236D0 (en) | 1985-01-18 |
GB8501246D0 (en) | 1985-02-20 |
HU190867B (en) | 1986-11-28 |
DK26185D0 (en) | 1985-01-18 |
ES540121A0 (en) | 1986-07-16 |
PT79844B (en) | 1986-10-23 |
DD228245A5 (en) | 1985-10-09 |
FI83635C (en) | 1991-08-12 |
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