NL8300392A - 1-Cyclohexyl-4-phenethyl:amino -1-butanone derivs. - Google Patents
1-Cyclohexyl-4-phenethyl:amino -1-butanone derivs. Download PDFInfo
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- NL8300392A NL8300392A NL8300392A NL8300392A NL8300392A NL 8300392 A NL8300392 A NL 8300392A NL 8300392 A NL8300392 A NL 8300392A NL 8300392 A NL8300392 A NL 8300392A NL 8300392 A NL8300392 A NL 8300392A
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- amino
- ethyl
- butanone
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 title claims 2
- 239000000651 prodrug Substances 0.000 claims abstract description 15
- 229940002612 prodrug Drugs 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 39
- -1 (1-methyl -2-phenylethyl) amino Chemical group 0.000 claims description 17
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 6
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 4
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 230000017858 demethylation Effects 0.000 claims description 2
- 238000010520 demethylation reaction Methods 0.000 claims description 2
- 238000003786 synthesis reaction Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims 2
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 claims 1
- 208000007101 Muscle Cramp Diseases 0.000 claims 1
- 208000005392 Spasm Diseases 0.000 claims 1
- 230000000397 acetylating effect Effects 0.000 claims 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims 1
- HUTZLSQBWQTKQN-SFHVURJKSA-N 1-cyclohexyl-4-[ethyl-[(2S)-1-phenylpropan-2-yl]amino]butan-1-one Chemical class C1(CCCCC1)C(CCCN([C@H](CC1=CC=CC=C1)C)CC)=O HUTZLSQBWQTKQN-SFHVURJKSA-N 0.000 abstract 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 3
- 239000005977 Ethylene Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-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
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- WAVYHSURRZBQKO-UHFFFAOYSA-N 1-cyclohexyl-4-[ethyl-[1-(4-methoxyphenyl)propan-2-yl]amino]butan-1-one Chemical compound C=1C=C(OC)C=CC=1CC(C)N(CC)CCCC(=O)C1CCCCC1 WAVYHSURRZBQKO-UHFFFAOYSA-N 0.000 description 2
- 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 description 2
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229950004117 secoverine Drugs 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ZVQOOHYFBIDMTQ-UHFFFAOYSA-N [methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-lambda(6)-sulfanylidene]cyanamide Chemical compound N#CN=S(C)(=O)C(C)C1=CC=C(C(F)(F)F)N=C1 ZVQOOHYFBIDMTQ-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- HYTACLVSJIFYBY-UHFFFAOYSA-N azane;dichloromethane;methanol Chemical compound N.OC.ClCCl HYTACLVSJIFYBY-UHFFFAOYSA-N 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 210000001520 comb Anatomy 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000004262 preparative liquid chromatography Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 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 description 1
- 125000001302 tertiary amino group Chemical group 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
- C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D317/28—Radicals substituted by nitrogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
,p « DIR 0344 NIEUWE SPASMOLYTISCH WERKZAME PROPYLCYCLOHEXYLKETONDERIVATEN, . De uitvinding heeft betrekking op nieuwe 1- -cyclohexyl-4- jethyK 1-methyl-2- f.enylethyl) aminój -1-butanon-derivaten met spasmolytische werking, op een werkwijze ter bereiding van deze verbindingen, en op farmaceutische prepa-5 raten die deze verbindingen als werkzame stof bevatten., p «DIR 0344 NEW SPASMOLYTICALLY ACTIVE PROPYLCYCLOHEXYL KETT DERIVATIVES,. This invention relates to novel 1-cyclohexyl-4-methyl-1-methyl-2-phenyl-ethyl-amino-1-butanone derivatives having an antispasmodic action, to a method of preparing these compounds, and to pharmaceutical prepa-5 combs containing these compounds as active substances.
Uit de Nederlandse octrooiaanvrage 7404733 is een groep spasmolytisch werkzame verbindingen met formule 1 van het formuleblad bekend, waarin R^ t/m Rg en X onder andere de in formule 2 aangegeven betekenis kunnen hebben. Het 10 hydrochloride van de verbinding met formule 2 is bekend onder de naam secoverine.Dutch patent application 7404733 discloses a group of spasmolytically active compounds of formula 1 of the formula sheet, in which R 1 to R 9 and X may have, inter alia, the meaning indicated in formula 2. The hydrochloride of the compound of formula II is known under the name secoverine.
De uitvinding betreft nu verbindingen met formule 3 van het formuleblad, waarin R de methoxy-of hydroxygroep, 15 Rf een hydroxygroep op de 2-, 3- of 4-plaats van de cyclohexyl-groep voorstellen, en waarin de groep (1-methyl-2-fenylethyl)amino de S-configu-ratie bezit, prodrugs daarvan en hun farmaceutisch aanvaardbare zouten.The invention now relates to compounds of formula 3 of the formula sheet, in which R represents the methoxy or hydroxy group, Rf represents a hydroxy group in the 2-, 3- or 4-position of the cyclohexyl group, and in which the group (1-methyl -2-phenylethyl) amino has the S configuration, prodrugs thereof and their pharmaceutically acceptable salts.
20 Gevonden werd dat deze verbindingen een spasmo lytische werking hebben die langduriger is, dan die van de struktureel nauw verwante, bekende verbinding secoverine, terwijl de intrinsieke aktiviteit ermee vergelijkbaar is.These compounds have been found to have a spasmolytic activity that is longer lasting than that of the structurally closely related, known compound secoverine, while the intrinsic activity is comparable to it.
Dit geldt in het bijzonder de verbinding met 25 formule 3, waarin R de methoxygroep en R' de hydroxygroep voorstellen. Bij een geschikte prodrug-vorm wordt onder andere de kinetiek extra gunstig beïnvloed, omdat de moederver-binding geleidelijk via hydrolyse uit de prodrugvorm vrijkomt (vergelijk T. Higuchi and V. Stella: Prodrugs as Novel 30 Drug Delivery Systems 1975).This is especially true of the compound of formula 3, wherein R represents the methoxy group and R 'represents the hydroxy group. In a suitable prodrug form, among other things, the kinetics are influenced extra favorably, because the parent compound is gradually released from the prodrug form via hydrolysis (compare T. Higuchi and V. Stella: Prodrugs as Novel 30 Drug Delivery Systems 1975).
Van de bovenbeschreven verbindingen met formule 3 kunnen prodrug-derivaten verkregen worden door de hydroxy-groepen R en/of R’ om te zetten in bijvoorbeeld .een ester-groep of een urethaangroep.From the compounds of formula 3 described above, prodrug derivatives can be obtained by converting the hydroxy groups R and / or R 'into, for example, an ester group or a urethane group.
35 Andere prodrugs kunnen worden verkregen door derivatisering van de keto-functie tot bijv. een acetaal, of van de tertiaire amino-functie tot metabool labiele ammonium-derivaten.Other prodrugs can be obtained by derivatizing the keto function to eg an acetal, or from the tertiary amino function to metabolically labile ammonium derivatives.
8300392 -2-8300392 -2-
, ♦ V, ♦ Q
De verbindingen met formule 3 bevatten tenminste één efi soms drie chirale centra» Bovendien veroorzaakt, een hydroxygroep R' in de cyclohexylring cis-trans isomerie. De uitvinding heeft zowel betrekking op mengsels van stereo-iso-5 meren als op de afzonderlijke componenten van dergelijke mengsels»The compounds of formula 3 sometimes contain at least one ephi three chiral centers. In addition, a hydroxy group R 'in the cyclohexyl ring causes cis-trans isomerism. The invention relates both to mixtures of stereoisomers and to the individual components of such mixtures.
De verbindingen met formule -3 en zijn prodrug-vormen kunnen op voor de synthese van analoge verbindingen bekende wijze worden bereid. Verbindingen met formule 3 10 kunnen bijvoorbeeld verkregen worden door reactie van de verbinding met formule 4, waarin R de bovengenoemde betekenis heeft, met een verbinding met de formule 5, waarin de hydroxygroep zich op de 2-, 3- of 4-plaats van de cyclohexylring kan bevinden.The compounds of formula -3 and its prodrug forms can be prepared in a manner known for the synthesis of analogous compounds. For example, compounds of formula III can be obtained by reacting the compound of formula 4, wherein R has the above meaning, with a compound of formula 5, wherein the hydroxy group is in the 2-, 3- or 4-position of the cyclohexyl ring.
15 De verbindingen met formule 3 waarin zowel RThe compounds of formula 3 wherein both R
als R’ een hydroxygroep voorstellen kunnen bijvoorbeeld ook verkregen worden door demethylering van de overeenkomstige verbindingen waarin R de methoxygroep is.if R 'represent a hydroxy group, it can also be obtained, for example, by demethylation of the corresponding compounds in which R is the methoxy group.
Prodrug-vormen kunnen worden verkregen door 20 derivatisering van verbindingen met de formule 3 of door uit te gaan van gederivatiseerde tussenprodukten. Zo kan bijvoorbeeld een verbinding met de formule 3 waarin R een methoxy en R' een hydroxygroep voorstellen, worden geacyleerd met een zuurchloride. Ook kan voor een verbinding van de formule 25 3 waarvan de keto groep is geacetaliseerd bijvoorbeeld worden uitgegaan van een verbinding van de formule 5.Prodrug forms can be obtained by derivatization of compounds of the formula 3 or starting from derivatized intermediates. For example, a compound of formula 3 wherein R represents a methoxy and R 'represents a hydroxy group can be acylated with an acid chloride. For a compound of the formula 25 whose keto group is acetalized, it is also possible, for example, to start from a compound of the formula 5.
De nieuwe spasmolytisch·werkzame verbindingen kunnen op de gebruikelijke wijze worden verwerkt in farmaceutische preparaten.The new spasmolytically active compounds can be incorporated in pharmaceutical preparations in the usual manner.
30 De uitvinding zal nu aan de hand van de volgende uitvoeringsvoorbeelden nader worden toegelicht.The invention will now be further elucidated on the basis of the following exemplary embodiments.
VOORBEELD IEXAMPLE I
A) Cis en trans 1 - ( 4-hydroxycyclohexyl)-4-£ethyl-S-|2-( 4-me-thoxyfenyl)-1-methylethyl aminoj-1 -butanon ethyleencyclo-35 acetaal.A) C18 and trans 1- (4-hydroxycyclohexyl) -4-ethyl-S- 2- (4-methoxyphenyl) -1-methyl-ethyl-amino-1-butanone ethylene cyclo-35 acetal.
Een oplossing van 1,2 g S-2-(4-methoxyfenyl)-1-methyl diethylamine, 1,6 g 4-chloor-1-(4-hydroxycyclohexyl) -1-butanon ethyleencycloacetaal, 0.9 g kaliumcarbonaat en 8 3 0 0 3 9 2' ' -ϊ * » ? * '# -3- 0,9 g natriumjodide in 10 ml dimethylformamide werd gedurende 24 uren onder roeren verwarmd op een temperatuur van 70°C. Na afkoelen tot kamertemperatuur werd 50 ml water toegevoegd en het reactiemengsel werd driemaal ge-5 extraheerd met porties van 50 ml methyleenehloride. Door van het extract het oplosmiddel door destillatie onder verminderde druk te verwijderen, werd na zuivering via kolomchromatografie het bovengenoemde ethyleencycloacetaal verkregen.A solution of 1.2 g of S-2- (4-methoxyphenyl) -1-methyl diethylamine, 1.6 g of 4-chloro-1- (4-hydroxycyclohexyl) -1-butanone ethylene cycloacetal, 0.9 g of potassium carbonate and 8 3 0 0 3 9 2 '' -ϊ * »? 0.9 g of sodium iodide in 10 ml of dimethylformamide was heated to a temperature of 70 ° C with stirring for 24 hours. After cooling to room temperature, 50 ml of water was added and the reaction mixture was extracted three times with 50 ml portions of methylene chloride. By removing the solvent from the extract by distillation under reduced pressure, the above ethylene cycloacetal was obtained after purification by column chromatography.
10 B) Cis en trans 1-(4-hydroxycyclohexyl)-4-^ethyl-5 -methoxyfenyl)-1-methylethyrj aminoj-1-butanon.B) Cis and trans 1- (4-hydroxycyclohexyl) -4-ethyl-5-methoxyphenyl) -1-methyl-ethyl-amino-1-butanone.
De volgens voorbeeld I-A verkregen oplossing van het cycloacetaal in methyleenchloride werd gehydrolyseerd 15 door het na toevoegen van 50 ml 2 N zoutzuur gedurende 24 uren te roeren.The solution of the cycloacetal in methylene chloride obtained according to example I-A was hydrolysed by stirring for 24 hours after adding 50 ml of 2 N hydrochloric acid.
Vervolgens werd het inhomogene mengsel geneutraliseerd met geconcentreerde ammonia, de organische laag werd afgescheiden, gedroogd op natriumsulfaat en onder verminderde druk 20 ingedampt.Then the inhomogeneous mixture was neutralized with concentrated ammonia, the organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure.
De verkregen base van bovengenoemde verbinding werd verder gezuiverd door middel van kolomchromatografie over silica-gel met als elutiemiddel methyleenchloride-methanol-ammo-nia (92:7,5:0,5) .The resulting base of the above compound was further purified by column chromatography over silica gel using methylene chloride-methanol-ammonia (92: 7.5: 0.5) as the eluent.
25 Op deze wijze werd een cis-trans isomerenmengsel in de ver houding van 1:3 verkregen.In this way, a cis-trans isomer mixture in the ratio of 1: 3 was obtained.
De afzonderlijke cis en trans.isomeren werden verkregen door scheiding met behulp van preparatieve vloeistof chro-matografie.The individual cis and trans isomers were obtained by separation by preparative liquid chromatography.
30 VOORBEELD IIEXAMPLE II
Cis en trans 1-(3-hydroxycyclohexyl)-4-fethyl-S -β- (4-methoxyfenyl}-1-methylethyl]amino'-1-butanon en zijn ethy-leencycloacetaal.Cis and trans 1- (3-hydroxycyclohexyl) -4-ethyl-S-β- (4-methoxyphenyl} -1-methylethyl] amino-1-butanone and its ethylene cycloacetal.
Op analoge wijze als beschreven in voorbeeld I 35 werden door condensatie met 4-chloor-1~(3-hydroxycyclohexyl) -1-butanon de afzonderlijke cissen trans-vorm van bovengenoemde verbindingen verkregen, elk in de vorm van een dia-stereoisomeren mengsel.In an analogous manner as described in Example I 35, by condensation with 4-chloro-1 (3-hydroxycyclohexyl) -1-butanone, the individual cis trans form of the above compounds were obtained, each in the form of a dia-stereoisomer mixture.
83003928300392
VOORBEELD IIIEXAMPLE III
Cis en trans 1 - (4-hydroxycyclohexyl) -4--^ethyl-S -jg-( 4-hydro-xyfenyl)-1-methylethyl| aminoj-1-butanon en zijn ethyleency-cloacetaal.Cis and trans 1 - (4-hydroxycyclohexyl) -4 - ^ ethyl-S-yg- (4-hydro-xyphenyl) -1-methyl-ethyl | amino-1-butanone and its ethylene cyclo-acetal.
5 Op de in voorbeeld I beschreven wijze w.erden door reactie van 2,84 g 4-ehloor-1 -(4-h.ydroxycyclohexyl.)-1 -butanon ethyleencycloacetaal en 2,16 g S-2-(4-hydroxyfenyl) -1- raethyldiethylamine het cis en trans stereoisomeren mengsel van de bovengenoemde verbindingen verkregen in de vorm 10 van vrijwel kleurloze oliën.In the manner described in example I, reaction of 2.84 g of 4-chloro-1- (4-hydroxycyclohexyl) -1-butanone ethylene cycloacetal and 2.16 g of S-2- (4-hydroxyphenyl) -1-raethyldiethylamine is the cis and trans stereoisomer mixture of the above compounds obtained in the form of substantially colorless oils.
VOORBEELD IVEXAMPLE IV
Trans-1 -(4-acetoxycyclohexyl)-4-£ethyl-S (4-methoxyfenyl) -1-methylethyï3 aminoj-1-butanon.Trans-1- (4-acetoxycyclohexyl) -4-ethyl-S (4-methoxyphenyl) -1-methyl-ethyl-amino-1-butanone.
Aan een oplossing van 0,7 g van het volgens 15 voorbeeld I-B verkregen trans-1-(4-hydroxycyclohexyl)-4- >jethyl-S-[i- ( 4-methoxyf enyl) -1-methylethyl^ amino] -1 -butanon in een mengsel van 5 ml tolueen en 8 ml methyleenchloride werd onder roeren bij kamertemperatuur 0,8 ml pyridine en daarna 0,2 ml acetylchloride toegevoegd.To a solution of 0.7 g of the trans-1- (4-hydroxycyclohexyl) -4-> methyl-S- [1- (4-methoxyphenyl) -1-methylethyl-amino] -1 obtained according to example IB -butanone in a mixture of 5 ml of toluene and 8 ml of methylene chloride was added with stirring at room temperature 0.8 ml of pyridine and then 0.2 ml of acetyl chloride.
» » 20 Na 16 uren werd het reactiemengsel onder ver minderde druk ingedampt en het verkregen residue gemengd met 30 ral ether. Het mengsel werd daarna gewassen met verdunde natriumbicarbonaat-oplossing. De verkregen etherische oplossing werd gedroogd met watervrij natriumsulfaat en vervolgens 25 onder verminderde druk ingedampt·.After 20 hours, the reaction mixture was evaporated under reduced pressure and the residue obtained was mixed with 30 ether. The mixture was then washed with dilute sodium bicarbonate solution. The ethereal solution obtained was dried with anhydrous sodium sulfate and then evaporated under reduced pressure.
Door zuivering van het concentraat via kolomchromatografie werd de bovengenoemde verbinding als een vrijwel kleurloze olie verkregen.Purification of the concentrate by column chromatography gave the above compound as a nearly colorless oil.
30 35 8 3 0 0 39 230 35 8 3 0 0 39 2
Claims (7)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8300392A NL8300392A (en) | 1983-02-03 | 1983-02-03 | 1-Cyclohexyl-4-phenethyl:amino -1-butanone derivs. |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8300392A NL8300392A (en) | 1983-02-03 | 1983-02-03 | 1-Cyclohexyl-4-phenethyl:amino -1-butanone derivs. |
| NL8300392 | 1983-02-03 |
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| Publication Number | Publication Date |
|---|---|
| NL8300392A true NL8300392A (en) | 1984-09-03 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8300392A NL8300392A (en) | 1983-02-03 | 1983-02-03 | 1-Cyclohexyl-4-phenethyl:amino -1-butanone derivs. |
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| Country | Link |
|---|---|
| NL (1) | NL8300392A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0289070A1 (en) * | 1987-04-10 | 1988-11-02 | Duphar International Research B.V | Tertiary arylethyl amine derivatives having opiate-antagonistic activity |
-
1983
- 1983-02-03 NL NL8300392A patent/NL8300392A/en not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0289070A1 (en) * | 1987-04-10 | 1988-11-02 | Duphar International Research B.V | Tertiary arylethyl amine derivatives having opiate-antagonistic activity |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A1B | A search report has been drawn up | ||
| A85 | Still pending on 85-01-01 | ||
| BV | The patent application has lapsed |