NL8304392A - 1-Isopropyl-amino-3-aryloxy-2-propanol(s) prodn. - for use as beta-blockers, by reacting 3-(N-isopropyl-N-benzhydrylamino)-1,2-epoxy-propane with phenolic cpd. - Google Patents
1-Isopropyl-amino-3-aryloxy-2-propanol(s) prodn. - for use as beta-blockers, by reacting 3-(N-isopropyl-N-benzhydrylamino)-1,2-epoxy-propane with phenolic cpd. Download PDFInfo
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- NL8304392A NL8304392A NL8304392A NL8304392A NL8304392A NL 8304392 A NL8304392 A NL 8304392A NL 8304392 A NL8304392 A NL 8304392A NL 8304392 A NL8304392 A NL 8304392A NL 8304392 A NL8304392 A NL 8304392A
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- isopropyl
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- benzhydrylamino
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- WSMBTEDNTPDCJM-UHFFFAOYSA-N n-benzhydryl-n-(oxiran-2-ylmethyl)propan-2-amine Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)N(C(C)C)CC1CO1 WSMBTEDNTPDCJM-UHFFFAOYSA-N 0.000 title claims abstract description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 title abstract description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 title abstract description 3
- 239000002876 beta blocker Substances 0.000 title 1
- 229940097320 beta blocking agent Drugs 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 5
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229960005235 piperonyl butoxide Drugs 0.000 claims abstract description 3
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 3
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 9
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- -1 benzhydryl group Chemical group 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 239000012299 nitrogen atmosphere Substances 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000004593 Epoxy Substances 0.000 abstract 1
- 101100109871 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) aro-8 gene Proteins 0.000 abstract 1
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 abstract 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 abstract 1
- 239000000047 product Substances 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- QILSFLSDHQAZET-UHFFFAOYSA-N diphenylmethanol Chemical compound C=1C=CC=CC=1C(O)C1=CC=CC=C1 QILSFLSDHQAZET-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 description 1
- QNFVQJPWLUTYNN-UHFFFAOYSA-N 1-[benzhydryl(propan-2-yl)amino]-3-chloropropan-2-ol Chemical compound C=1C=CC=CC=1C(N(CC(O)CCl)C(C)C)C1=CC=CC=C1 QNFVQJPWLUTYNN-UHFFFAOYSA-N 0.000 description 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 description 1
- NPEGHCREQHYERS-UHFFFAOYSA-N 2-(2-hydroxyphenyl)acetamide Chemical compound NC(=O)CC1=CC=CC=C1O NPEGHCREQHYERS-UHFFFAOYSA-N 0.000 description 1
- FAYGEALAEQKPDI-UHFFFAOYSA-N 4-(2-methoxyethyl)phenol Chemical compound COCCC1=CC=C(O)C=C1 FAYGEALAEQKPDI-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- RDRZAYABFBGPDQ-UHFFFAOYSA-N C(C)(C)N(C(C1=CC=CC=C1)C1=CC=CC=C1)CC(COC1=C(C=C(C=C1)NC(CCC)=O)C(C)=O)O Chemical compound C(C)(C)N(C(C1=CC=CC=C1)C1=CC=CC=C1)CC(COC1=C(C=C(C=C1)NC(CCC)=O)C(C)=O)O RDRZAYABFBGPDQ-UHFFFAOYSA-N 0.000 description 1
- OOQNFLSZMQVWEP-UHFFFAOYSA-N C(C)(C)N(C(C1=CC=CC=C1)C1=CC=CC=C1)CC(COC1=CC=C(C=C1)CC(N)=O)O Chemical compound C(C)(C)N(C(C1=CC=CC=C1)C1=CC=CC=C1)CC(COC1=CC=C(C=C1)CC(N)=O)O OOQNFLSZMQVWEP-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N [chloro(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Cl)C1=CC=CC=C1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 description 1
- 229960002122 acebutolol Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229960002274 atenolol Drugs 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- FGWZEOPEZISTTR-UHFFFAOYSA-N n-(3-acetyl-4-hydroxyphenyl)butanamide Chemical compound CCCC(=O)NC1=CC=C(O)C(C(C)=O)=C1 FGWZEOPEZISTTR-UHFFFAOYSA-N 0.000 description 1
- DAEFOQDMAOMQFU-UHFFFAOYSA-N n-benzhydrylpropan-2-amine Chemical compound C=1C=CC=CC=1C(NC(C)C)C1=CC=CC=C1 DAEFOQDMAOMQFU-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000007858 starting material Substances 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
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/36—Compounds containing oxirane rings with hydrocarbon radicals, substituted by nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
- C07C217/30—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
P -. 1 * k % **P -. 1 * k% **
Korte aanduiding: Werkwijze voor de bereiding van 1-isopropyl-amino—3—aryloxy—2—popanolen, alsmede tussenverbinding die in deze werkwijze gebruikt kan wordenShort designation: Process for the preparation of 1-isopropylamino-3-aryloxy-2-popanols, as well as intermediate compound which can be used in this process
De uitvinding heeft betrekking op een nieuwe werkwijze voor de bereiding van l-isopicpylainino-3-aryloxy-2-piEpanolen van formule 1, waarin Ar een gesubstitueerde aromatische rest voorstelt.The invention relates to a new process for the preparation of 1-isopicpylainino-3-aryloxy-2-pipanols of formula 1, wherein Ar represents a substituted aromatic residue.
5 De uitvinding heeft tevens betrekking op een nieuwe verbinding, 3-(N-isopropyl-N-benzhydrylamino)-l,2-epoxypropaan, van formule 2.The invention also relates to a new compound, 3- (N-isopropyl-N-benzhydrylamino) -1,2-epoxypropane, of formula 2.
Verbindingen van formule 1 zijn waardevolle geneesmiddelen, zogenaamde y3-blockers. Werkwijzen voor de bereiding daarvan 10 zijn bijvoorbeeld beschreven in de Britse octrooischriften 1 247 384 en 1 285 038 en in het Zweedse octrooischrift 354 851.Compounds of formula 1 are valuable drugs called y3 blockers. Methods for their preparation are described, for example, in British Pat. Nos. 1,247,384 and 1,285,038 and in Swedish Pat. No. 354,851.
Thans is een nieuwe werkwijze uitgevonden voor de bereiding van verbindingen van formule 1. In deze werkwijze laat 15 men een verbinding van formule 2 reageren met een verbinding van formule 3, waarin Ar een gesubstitueerde aromatische rest is.A new process has now been invented for the preparation of compounds of formula 1. In this process, a compound of formula 2 is reacted with a compound of formula 3, wherein Ar is a substituted aromatic residue.
Het produkt van deze reactie is een verbinding van formule 4.The product of this reaction is a compound of formula 4.
De benzhydrylgroep van deze verbinding kan onder milde om-20 standigheden worden verwijderd, bijvoorbeeld door middel van mierezuur of azijnzuur of door katalytische hydrogenéring. Benzhydrol wordt gevormd tijdens het verwijderen en dit kan worden teruggewonnen en opnieuw worden omgezet in benzhydryl-chloride of -bromide.The benzhydryl group of this compound can be removed under mild conditions, for example, by means of formic acid or acetic acid or by catalytic hydrogenation. Benzhydrol is formed during removal and can be recovered and converted back to benzhydryl chloride or bromide.
25 Het voornaamste voordeel van de werkwijze volgens de uitvinding isdat het nu mogelijk is eerst een tussenverbinding te bereiden , waaraan vervolgens het duurste gedeelte van de verbinding, de fenolcomponent, wordt toegevoegd. Dit tussen-product van formule 2 is voor alle gewenste eindprodukten 30 hetzelfde. Het is dus gemakkelijk alle verschillende^-blockers te bereiden onder toepassing van slechts één uitgangsmateriaal, de tussenverbinding van formule 2. De eindprodukten kunnen in hoge opbrengsten worden verkregen en de werkwijze is dus ook economisch aantrekkelijk.The main advantage of the method according to the invention is that it is now possible to first prepare an intermediate compound, to which the most expensive part of the compound, the phenol component, is then added. This intermediate of formula 2 is the same for all desired end products. Thus, it is easy to prepare all the different blockers using only one starting material, the intermediate of formula 2. The final products can be obtained in high yields and the process is thus also economically attractive.
8304392 —-18304392-1
OO
- 2 -- 2 -
De voorkeur verdienende reactieomstandigheden zijn: reactietemperatuur ca. 130°C, inerte atmosfeer (bijvoorbeeld stikstofatmosfeer) en de aanwezigheid van een alkalische katalysator, zoals natrium- of kalium-tert. butoxide.Preferred reaction conditions are: reaction temperature about 130 ° C, inert atmosphere (e.g. nitrogen atmosphere) and the presence of an alkaline catalyst, such as sodium or potassium tert. butoxide.
5 De volgende voorbeelden beschrijven in detail de berei ding van de tussenverbinding alsook de bereiding van de eindproducten .The following examples describe in detail the preparation of the intermediate compound as well as the preparation of the final products.
Voorbeeld IExample I
Bereiding van de tussenverbinding van formule 2 10 a) l-chloor-3-(N-isopropyl-N-benzhydrylamino)-2-propanol 590 g(6,4 mol) l-chloor-2,3-epoxypropaan en 225 g (1 mol) isopropylbenzhydrylamine werden 20 uur op 120°C verwarmd onder terugvloeiing. De overmaat l-chloor-2,3-epoxypropaan werd onder verminderde druk verwijderd, waarbij 318 g (ca.Preparation of the intermediate of formula 2 10 a) 1-chloro-3- (N-isopropyl-N-benzhydrylamino) -2-propanol 590 g (6.4 mol) 1-chloro-2,3-epoxypropane and 225 g ( 1 mol) isopropylbenzhydrylamine was heated at reflux for 20 hours at 120 ° C. The excess of 1-chloro-2,3-epoxypropane was removed under reduced pressure to yield 318 g (ca.
15 100%) van het gewenste produkt werd verkregen in de vorm van een viskeuze olie; kookpunt 150°C/0,2 mm (gedeeltelijke ontleding).100%) of the desired product was obtained in the form of a viscous oil; boiling point 150 ° C / 0.2 mm (partial decomposition).
b) 3-(N-isopropyl-N-benzhydrylamino)-l,2-epoxypropaan 318 g(l mol) van het in stap a) verkregen ruwe produkt 20 en 112 g (1 mol) kalium-tert. butoxide werden 5 uur verwarmd op 70°C- in 1000 ml dimethylaceetamide. Het kaliumchloride werd gefiltreerd en de oplosmiddelen werden bij verminderde druk uit het filtraat verdampt, waardoor 280 g (ca. 100%) van het gewenste produkt werd verkregen in de vorm van een 25 viskeuze olie; kookpunt 128°C/0,15 mm.b) 3- (N-isopropyl-N-benzhydrylamino) -1,2-epoxypropane 318 g (1 mol) of the crude product obtained in step a) and 112 g (1 mol) potassium tert. butoxide was heated at 70 ° C for 5 hours in 1000 ml dimethylacetamide. The potassium chloride was filtered and the solvents evaporated from the filtrate under reduced pressure to give 280 g (about 100%) of the desired product in the form of a viscous oil; boiling point 128 ° C / 0.15 mm.
Voorbeeld IIExample II
a) l-(N-isopropyl-N-'benzhydrylamino)-3-(2-acetyl-4-butyramido-fenoxy)-2-propanol 28,1 g(0,l mol) van het in stap b) van voorbeeld I ver-30 kregen ruwe produkt en 22,1 g (0,1 mol) 2-acetyl-4-butyramido-fenol, alsmede 0,3 g kalium-tert. butoxide in 17 ml DMA werden 20 uur op 130°C verwarmd onder een stikstofstroom. Het reactie-mengsel werd opgelost in 250 ml tolueen en gewassen met een verdunde NaOH-oplossing en water. Het oplosmiddel werd bij 35 verminderde druk verwijderd, waarbij 48,0 g (96%) van het gewenste produkt werd verkregen; (het product kan worden gekristalliseerd uit ether) smeltpunt 115-117°C.a) 1- (N-isopropyl-N-benzhydrylamino) -3- (2-acetyl-4-butyramido-phenoxy) -2-propanol 28.1 g (0.1 mol) of the step b) of Example Crude product and 22.1 g (0.1 mole) of 2-acetyl-4-butyramido-phenol and 0.3 g of potassium tert were obtained. butoxide in 17 ml DMA were heated at 130 ° C under nitrogen flow for 20 hours. The reaction mixture was dissolved in 250 ml of toluene and washed with a dilute NaOH solution and water. The solvent was removed under reduced pressure to obtain 48.0 g (96%) of the desired product; (the product can be crystallized from ether) mp 115-117 ° C.
b) l-isopropylamino-3-(2-acetyl-4-butyramidofenoxy)-2-propanol (acebutolol) *53 0 4 3 9 2 __ ____£ - 3 - V* -4 25.0 g (0,05 mol) van het in stap a) verkregen produkt en 1 g 10% palladium-koolstof-katalysator in 100 ml methanol werden bij normale temperatuur en druk 2 tot 3 uur gehydro-geneerd in een waterstofatmosfeer. Het mengsel werd gefiltreerd 5 en het oplosmiddel werd bij verminderde druk verwijderd. Het residu werd opgelost in IN zoutzuur en met methyleenchloride geëxtraheerd. De waterige laag werd behandeld met actieve kool, gefiltreerd en het filtraat werd alkalisch gemaakt met een NaOH-oplossing, waarbij het gewenste produkt kristalliseerde; 10 opbrengst 16,0 g (95%), smeltpunt 119-122°C.b) 1-isopropylamino-3- (2-acetyl-4-butyramidophenoxy) -2-propanol (acebutolol) * 53 0 4 3 9 2 __ ____ £ - 3 - V * -4 25.0 g (0.05 mol) of the product obtained in step a) and 1 g of 10% palladium carbon catalyst in 100 ml of methanol were hydrogenated at a normal temperature and pressure for 2 to 3 hours in a hydrogen atmosphere. The mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in 1N hydrochloric acid and extracted with methylene chloride. The aqueous layer was treated with activated charcoal, filtered and the filtrate was made alkaline with a NaOH solution, whereby the desired product crystallized; Yield 16.0 g (95%), mp 119-122 ° C.
Voorbeeld IIIExample III
a) 1(N-isopropy1-N-benzhydrylamino)-3-/4-(2-methoxyethyl)-fenoxx7-2-propanol 28.1 g (0,1 mol) van het in stap b) van Voorbeeld I ver-15 kregen produkt en 15,2 g (0,1 mol) 4-(2-methoxyethyl)fenol, alsmede 0,3 g kalium-tert. butoxide in 20 ml DMA werden 20 uur op 130°C verwarmd. Scheiding werd uitgevoerd als in Voorbeeld II, stap a), waarbij 42,0 g (97%) van het gewenste produkt werd verkregen in de vorm van een viskeuze olie.a) 1 (N-isopropy1-N-benzhydrylamino) -3- / 4- (2-methoxyethyl) -phenoxx7-2-propanol 28.1 g (0.1 mol) of the mixture obtained in step b) of Example I product and 15.2 g (0.1 mol) of 4- (2-methoxyethyl) phenol, as well as 0.3 g of potassium tert. butoxide in 20 ml DMA were heated at 130 ° C for 20 hours. Separation was carried out as in Example II, step a), whereby 42.0 g (97%) of the desired product were obtained in the form of a viscous oil.
20 b) l-isopropylamino-3-/5-(2-methoxyethyl)fenox£7-2-propanol (methoprolol)B) 1-isopropylamino-3- / 5- (2-methoxyethyl) phenox £ 7-2-propanol (methoprolol)
De benzhydrylgroep van het produkt van stap a) werd verwijderd als in Voorbeeld II, stap b). Het mengsel werd gefiltreerd en het oplosmiddel werd onder verminderde druk verwij-25 derd. Het residu werd opgelost in IN zoutzuur en geëxtraheerd met methyleenchloride om het benzhydrol of difenylmethaan te verwijderen. De waterige oplossing werd alkalisch gemaakt en het produkt werd met tolueen geëxtraheerd. Het oplosmiddel werd bij verminderde druk verwijderd, waardoor het gewenste 30 produkt werd verkregen; smeltpunt ca, 45°C, opbrengst 95%.The benzhydryl group of the product of step a) was removed as in Example II, step b). The mixture was filtered and the solvent was removed under reduced pressure. The residue was dissolved in 1N hydrochloric acid and extracted with methylene chloride to remove the benzhydrol or diphenylmethane. The aqueous solution was made alkaline and the product was extracted with toluene. The solvent was removed under reduced pressure to give the desired product; melting point approx. 45 ° C, yield 95%.
Voorbeeld IVExample IV
1- (N-isopropyl-N-benzhydrylamino)-3-(4-carbamoylmethylfenoxy)- 2- propanol1- (N-isopropyl-N-benzhydrylamino) -3- (4-carbamoylmethylphenoxy) -2-propanol
De procedure was analoog aan de procedure van Voorbeeld 35 II, stap a) en er werd 28,1 g van de verbinding van formule 2 en 15,1 g carbamoylmethylfenol gebruikt, waardoor 42,3 g(98%) van het gewenste produkt werd verkregen in de vorm van een viskeuze olie.The procedure was analogous to the procedure of Example 35 II, step a) and 28.1 g of the compound of formula 2 and 15.1 g of carbamoylmethylphenol were used, yielding 42.3 g (98%) of the desired product obtained in the form of a viscous oil.
8304392 ,- *w V.8304392 * w V.
> - 4 - b) 1-i sopropylaraino-3-( 4-car bamoylmethylfenoxy)-2-propanol (atenolol)> - 4 - b) 1-sopropylaraino-3- (4-carbamoylmethylphenoxy) -2-propanol (atenolol)
De procedure was als in Voorbeeld II, stap b), waarbij het gewenste produkt werd verkregen; opbrengst 94%, smeltpunt 5 146-148°C.The procedure was as in Example II, step b) to obtain the desired product; yield 94%, mp 146-148 ° C.
83043928304392
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI824411A FI66839C (en) | 1982-12-22 | 1982-12-22 | PROCEDURE FOR THERAPEUTIC ADMINISTRATION OF THERAPEUTIC ANALYTICAL PRODUCTS AVOID 1-ISOPROPYLAMINO-3-PHENOXY-2-PROPANOLER SAMT MELLA NPODUKT |
| FI824411 | 1982-12-22 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NL8304392A true NL8304392A (en) | 1984-07-16 |
Family
ID=8516499
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NL8304392A NL8304392A (en) | 1982-12-22 | 1983-12-21 | 1-Isopropyl-amino-3-aryloxy-2-propanol(s) prodn. - for use as beta-blockers, by reacting 3-(N-isopropyl-N-benzhydrylamino)-1,2-epoxy-propane with phenolic cpd. |
Country Status (6)
| Country | Link |
|---|---|
| DD (1) | DD212957A5 (en) |
| DK (1) | DK586083A (en) |
| FI (1) | FI66839C (en) |
| NL (1) | NL8304392A (en) |
| SE (1) | SE8307129L (en) |
| SU (1) | SU1321371A3 (en) |
-
1982
- 1982-12-22 FI FI824411A patent/FI66839C/en not_active IP Right Cessation
-
1983
- 1983-12-20 DK DK586083A patent/DK586083A/en not_active Application Discontinuation
- 1983-12-21 NL NL8304392A patent/NL8304392A/en not_active Application Discontinuation
- 1983-12-21 SU SU833703901A patent/SU1321371A3/en active
- 1983-12-22 SE SE8307129A patent/SE8307129L/en not_active Application Discontinuation
- 1983-12-22 DD DD83258478A patent/DD212957A5/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| FI66839C (en) | 1984-12-10 |
| SE8307129L (en) | 1984-06-23 |
| DK586083D0 (en) | 1983-12-20 |
| FI66839B (en) | 1984-08-31 |
| FI824411L (en) | 1984-06-23 |
| SE8307129D0 (en) | 1983-12-22 |
| SU1321371A3 (en) | 1987-06-30 |
| DD212957A5 (en) | 1984-08-29 |
| DK586083A (en) | 1984-06-23 |
| FI824411A0 (en) | 1982-12-22 |
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