NO793871L - METHOD OF PREPARING METOPROL. - Google Patents
METHOD OF PREPARING METOPROL.Info
- Publication number
- NO793871L NO793871L NO793871A NO793871A NO793871L NO 793871 L NO793871 L NO 793871L NO 793871 A NO793871 A NO 793871A NO 793871 A NO793871 A NO 793871A NO 793871 L NO793871 L NO 793871L
- Authority
- NO
- Norway
- Prior art keywords
- formula
- compound
- propanol
- stated
- isopropylamino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- 150000001875 compounds Chemical class 0.000 claims description 24
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 229960002237 metoprolol Drugs 0.000 claims description 10
- -1 alkali metal methoxide Chemical class 0.000 claims description 9
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 9
- 239000003377 acid catalyst Substances 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical class CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical group 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000005228 aryl sulfonate group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical compound [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- NVSVLJBHRDKPOS-UHFFFAOYSA-N 2-[4-(oxiran-2-ylmethoxy)phenyl]ethyl 4-methylbenzenesulfonate Chemical compound S(=O)(=O)(C1=CC=C(C)C=C1)OCCC1=CC=C(OCC2CO2)C=C1 NVSVLJBHRDKPOS-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000007789 gas Substances 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
- 150000002894 organic compounds Chemical class 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- ISYORFGKSZLPNW-UHFFFAOYSA-N propan-2-ylazanium;chloride Chemical compound [Cl-].CC(C)[NH3+] ISYORFGKSZLPNW-UHFFFAOYSA-N 0.000 description 2
- 239000003087 receptor blocking agent Substances 0.000 description 2
- RRVCVIKEEIVNJV-UHFFFAOYSA-N 2-(4-hydroxyphenyl)ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCC1=CC=C(O)C=C1 RRVCVIKEEIVNJV-UHFFFAOYSA-N 0.000 description 1
- GSJKJPRTYNBOKU-UHFFFAOYSA-N 4-(2-chloroethyl)phenol Chemical compound OC1=CC=C(CCCl)C=C1 GSJKJPRTYNBOKU-UHFFFAOYSA-N 0.000 description 1
- CGQNVKGUSGZQJA-UHFFFAOYSA-N 4-methylbenzenesulfonic acid;propan-2-amine Chemical compound CC(C)N.CC1=CC=C(S(O)(=O)=O)C=C1 CGQNVKGUSGZQJA-UHFFFAOYSA-N 0.000 description 1
- IQXASIUYQZYQPH-UHFFFAOYSA-N CC1=CC=C(C=C1)S(=O)(=O)OC(C)C2=CC=C(C=C2)O Chemical compound CC1=CC=C(C=C1)S(=O)(=O)OC(C)C2=CC=C(C=C2)O IQXASIUYQZYQPH-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000007171 acid catalysis Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229940030602 cardiac therapy drug Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- XJRBAMWJDBPFIM-UHFFFAOYSA-N methyl vinyl ether Chemical group COC=C XJRBAMWJDBPFIM-UHFFFAOYSA-N 0.000 description 1
- 229960001300 metoprolol tartrate Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical class [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 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
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
- C07D303/18—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by etherified hydroxyl radicals
- C07D303/20—Ethers with hydroxy compounds containing no oxirane rings
- C07D303/24—Ethers with hydroxy compounds containing no oxirane rings with polyhydroxy compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
" Fremgangsmåte for fremstilling av metoprolol" "Method of Manufacture of Metoprolol"
Denne oppfinnelse angår en fremgangsmåte for fremstilling av 1-isopropylamino-3-[4-(2-metoksyetyl)fenoksy]-2-propanol eller metoprolol med formelen This invention relates to a process for the production of 1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]-2-propanol or metoprolol with the formula
samt sure addisjonssalter derav. as well as acid addition salts thereof.
Metoprolol er et terapeutisk verdifullt -såkalt 3-reseptor-blokkerende middel. De fleste 3-reseptor-blokk'erende midler har den ulempe at de foruten hjertets 3~reseptorer også blokkerer 3-reseptorene i blodkar og lunger. Metoprolol er derimot hjertespesifikk og er derfor et viktig legemiddel innen hjerte-terapien. Metoprolol is a therapeutically valuable so-called 3-receptor blocking agent. Most 3-receptor-blocking agents have the disadvantage that, in addition to the heart's 3-receptors, they also block the 3-receptors in blood vessels and lungs. Metoprolol, on the other hand, is heart-specific and is therefore an important drug in cardiac therapy.
Fremstillingen av metoprolol er kjent, f.eks. fra svensk patent 354.851, der 12 analogifremgangsmåter for dens fremstilling er beskrevet. Felles for disse metoder er at de alle angår fremgangsmåter for syntetisering av isopropylamino-sidekjeden. The preparation of metoprolol is known, e.g. from Swedish patent 354,851, where 12 analogous methods for its preparation are described. What these methods have in common is that they all relate to methods for synthesizing the isopropylamino side chain.
Foreliggende fremgangsmåte karakteriseres ved at en. forbindelse med formelen The present method is characterized by a. connection with the formula
der X er en reaktiv esterrest, omsettes med epiklorhydrin med formelen til en forbindelse med formelen som derefter omsettes med et surt addisjonssalt av isopropylamin til en forbindelse med formelen where X is a reactive ester residue, is reacted with epichlorohydrin of the formula to a compound of the formula which is then reacted with an acid addition salt of isopropylamine to a compound of the formula
og denne forbindelse omsettes til slutt med alkalimetallmetoksyd eller med metanol i nærvær av en sur katalysator til et sluttprodukt med formel I. and this compound is finally reacted with alkali metal methoxide or with methanol in the presence of an acid catalyst to a final product of formula I.
Fremgangsmåten kan beskrives med følgende formelskjerna: Den reaktive esterresten X kan være en alkyl- eller aryl-sulfonatgruppe, fordelaktig en tosylgruppe, og forbindelsen IV er da 1,2-epoksy-3-(4-tosyloksyetylfenoksy)-propan, som er en-ny organisk forbindelse med formelen The method can be described with the following formula core: The reactive ester residue X can be an alkyl or aryl sulfonate group, advantageously a tosyl group, and the compound IV is then 1,2-epoxy-3-(4-tosyloxyethylphenoxy)-propane, which is en- new organic compound with the formula
eller X er et halogenatom, fordelaktig et kloratom, og or X is a halogen atom, advantageously a chlorine atom, and
forbindelsen V er da l-isopropylamino-3-[4-(2-klorety1)-fenoksy]-2-propanol, som er en ny organisk forbindelse med formelen the compound V is then l-isopropylamino-3-[4-(2-chloroethyl)-phenoxy]-2-propanol, which is a new organic compound with the formula
Isopropylamin-syreaddisjonssaltet kan f.eks. være isopropylaminhydroklorid med formelen eller det kan være f.eks. isopropylamin-p-toluensulfonsyresalt med formelen The isopropylamine acid addition salt can e.g. be isopropylamine hydrochloride with the formula or it can be e.g. isopropylamine-p-toluenesulfonic acid salt with the formula
Alkalimetallmetoksydet kan f.eks. være kalium- eller natriummetoksyd, fordelaktig natriummetoksyd. Ved omsetning av metanol med forbindelser med formel V er f.eks. tørr HC1-gass eller p-toluensulfonsyre egnede syrekatalysatorer. The alkali metal methoxide can e.g. be potassium or sodium methoxide, preferably sodium methoxide. When reacting methanol with compounds of formula V, e.g. dry HCl gas or p-toluenesulfonic acid are suitable acid catalysts.
Spesielt karakteristisk for fremgangsmåten ifølge opp-finnelsen er at siste trinn i syntesekjeden vedrører metoksy-etylenden av molekylet, altså omsetningen mellom forbindelsen V og natriummetoksyd, eller mellom forbindelsen V og metanol i nærvær av en sur katalysator. Særlig karakteristisk for foreliggende fremgangsmåte er det at forbindelsen V er spesifikt - fremstilt fra forbindelsen IV ved omsetning av sistnevnte forbindelse ved nøytrale betingelser med et isopropylamin-syreaddis jonssalt . Det er videre karakteristisk for opp-finnelsen at spesielt ved "anvendelse av de ovenfor beskrevne syntesereaksjoner er råmaterialene for metoprololsyntesen billige og lett tilgjengelige, og hele synteseprosessen er derfor økonomisk. Particularly characteristic of the method according to the invention is that the last step in the synthesis chain concerns the methoxy-ethylene end of the molecule, i.e. the reaction between compound V and sodium methoxide, or between compound V and methanol in the presence of an acidic catalyst. Particularly characteristic of the present method is that the compound V is specifically prepared from the compound IV by reacting the latter compound under neutral conditions with an isopropylamine acid addition salt. It is further characteristic of the invention that, especially when using the above-described synthesis reactions, the raw materials for the metoprolol synthesis are cheap and easily available, and the whole synthesis process is therefore economical.
Det andre reaksjonstrinn av fremgangsmåten ifølge opp-finnelsen, der altså isopropylaminets sure addisjonssalt reagerer med en forbindelse med formel IV, er en spesifikk reaksjon med molekylets epoksydende. Det er naturligvis nød-vendig at reaksjonen er spesifikk for å hindre at isopropyl-amingruppen reagerer med den reaktive esterresten. Denne spesifisitet ble overraskende oppnådd da det ble funnet at molekylets epoksygruppe åpnet seg på riktig måte allerede ved nøytrale betingelser med sure addisjonssalter av isopropylamin. Omsetningen kan utføres ved å kombinere utgangsmaterialene og blande dem i et egnet oppløsningsmiddel til omsetningen er ferdig. For å akselerere reaksjonen er det fordelaktig å koke reaksjonsblandingen. Egnede oppløsningsmidler er f.eks. alkoholer så som etanol og isopropanol. The second reaction step of the method according to the invention, where the acid addition salt of the isopropylamine reacts with a compound of formula IV, is a specific reaction with the epoxide end of the molecule. It is of course necessary that the reaction be specific in order to prevent the isopropylamine group from reacting with the reactive ester residue. This specificity was surprisingly achieved when it was found that the molecule's epoxy group opened correctly already under neutral conditions with acid addition salts of isopropylamine. The reaction can be carried out by combining the starting materials and mixing them in a suitable solvent until the reaction is complete. To accelerate the reaction, it is advantageous to boil the reaction mixture. Suitable solvents are e.g. alcohols such as ethanol and isopropanol.
Det siste reaksjonstrinn, der altså f.eks. natriummetoksyd omsettes med forbindelsen V, utføres fordelaktig ved å koke i et egnet oppløsningsmiddel så som metanol, dimetylformamid, dimetylsulfoksyd eller en blanding av dem. The last reaction step, where e.g. sodium methoxide is reacted with compound V, is advantageously carried out by boiling in a suitable solvent such as methanol, dimethylformamide, dimethylsulfoxide or a mixture thereof.
Når omsetningen utføres med sur katalyse, omsettes f.eks. tilsvarende tosylatderivat med metanol i et egnet oppløsnings-middel så som metanol, ved blandingens kokepunkt i nærvær av en sur katalysator. Egnede syrekatalysatorer er f.eks. salt-syre eller p-toluensulfonsyre. When the conversion is carried out with acid catalysis, e.g. corresponding tosylate derivative with methanol in a suitable solvent such as methanol, at the boiling point of the mixture in the presence of an acid catalyst. Suitable acid catalysts are e.g. hydrochloric acid or p-toluenesulfonic acid.
Det første trinn i reaksjonsserien utføres ved vanlige metoder, f.eks. fra tilsvarende natriumfenolatderivat og epiklorhydrin i alkohol, f.eks. etanol, ved 20-30°C under om-røring. The first step in the reaction series is carried out by usual methods, e.g. from the corresponding sodium phenolate derivative and epichlorohydrin in alcohol, e.g. ethanol, at 20-30°C with stirring.
Ved foreliggende fremgangsmåte er det ikke nødvendig å isolere og rense mellomproduktene for å få et rent sluttprodukt, og fremgangsmåten er således også enkel i industriell målestokk. In the present method, it is not necessary to isolate and purify the intermediate products in order to obtain a pure end product, and the method is thus also simple on an industrial scale.
Det dannede amin I kan lett overføres til sure addisjonssalter ved omsetning med uorganiske eller organiske syrer. The formed amine I can easily be transferred to acid addition salts by reaction with inorganic or organic acids.
Fremgangsmåten beskrives nærmere i følgende eksempler: The procedure is described in more detail in the following examples:
Eksempel 1Example 1
a) 1,2-epoksy-3-(4-tosyloksyetylfenoksy)-propana) 1,2-epoxy-3-(4-tosyloxyethylphenoxy)-propane
2,6 g natrium oppløses i 200 ml absolutt etanol.2.6 g of sodium are dissolved in 200 ml of absolute ethanol.
26 g p-toluensulfonsyre-2-(4-hydroksyfenyl)-etylester og 10 g 26 g of p-toluenesulfonic acid 2-(4-hydroxyphenyl)-ethyl ester and 10 g
epiklorhydrin tilføres og omrøres i 25 timer ved ca. 25°C. Blandingen helles i vann, og produktet ekstraheres med metylen-klorid som tørkes med natriumsulfat. Oppløsningsmidlet av-destilleres'i vakuum, hvorved man får 1,2-epoksy-3-(4-tosyl-oksyetylf enoksy ) -propan i form av olje. epichlorohydrin is added and stirred for 25 hours at approx. 25°C. The mixture is poured into water, and the product is extracted with methylene chloride which is dried with sodium sulphate. The solvent is distilled off in a vacuum, whereby 1,2-epoxy-3-(4-tosyl-oxyethylphenoxy)-propane is obtained in the form of oil.
b) 1-isopropylamino-3-(4-tosyloksyetylfenoksy)-2-propanol-hydroklorid b) 1-isopropylamino-3-(4-tosyloxyethylphenoxy)-2-propanol hydrochloride
Oljen erholdt i foregående trinn oppløses i etanol, og 11 g isopropylamin-hydroklorid tilføres og det hele kokes i The oil obtained in the previous step is dissolved in ethanol, and 11 g of isopropylamine hydrochloride is added and the whole is boiled in
10 timer. Oppløsningsmidlet avdampes, hvorved man får 10 hours. The solvent is evaporated, whereby one obtains
l-isopropylamino-3-(4-tosyloksyetylfenoksy)-2-propanol-hydroklorid. 1-isopropylamino-3-(4-tosyloxyethylphenoxy)-2-propanol hydrochloride.
c) l-isopropylamino-3-[4-(2-metoksyety1)-fenoksy]-2-propanol Inndampningsresiduet fra foregående trinn oppløses i c) 1-isopropylamino-3-[4-(2-methoxyethyl)-phenoxy]-2-propanol The evaporation residue from the previous step is dissolved in
metanol, og 50 ml 30%ig natriummetoksyd i metanol og 30 ml dimetylformamid tilføres.Blandingen kokes i 20 timer, og oppløsningsmidlet avdampes. Residuet oppslemmes i vann, og produktet ekstraheres med kloroform. Kloroformekstrakten vaskes med vann, tørkes med natriumsulfat og inndampes til tørrhet. Inndampningsresiduet består'av metoprolol-base, methanol, and 50 ml of 30% sodium methoxide in methanol and 30 ml of dimethylformamide are added. The mixture is boiled for 20 hours, and the solvent is evaporated. The residue is slurried in water, and the product is extracted with chloroform. The chloroform extract is washed with water, dried with sodium sulfate and evaporated to dryness. The evaporation residue consists of metoprolol base,
som efter omkrystallisasjon fra f.eks. heptan, har' smeltepunkt. 45°C. Av denne fremstilles tartrat i vinsur aceton. Mefoprolol-tartratets smeltepunkt er ca. 120°C. which after recrystallization from e.g. heptane, has' melting point. 45°C. From this tartrate is prepared in tartaric acetone. Mefoprolol tartrate's melting point is approx. 120°C.
Ek sempel 2Oak sample 2
Fremgangsmåten foretas som i eksempel 1, bortsett fra at en ekvivalent mengde 4-(2-kloretyl)-fenol anvendes istedenfor 4-hydrpksyfeny1-etanoltosylat. The procedure is carried out as in example 1, except that an equivalent amount of 4-(2-chloroethyl)-phenol is used instead of 4-hydroxyphenyl-ethanol tosylate.
Eksempel 3 Example 3
l-isopropylamino-3-[4-(2-metoksyetyl)-fenoksy]-2-propanol 1-isopropylamino-3-[4-(2-methoxyethyl)-phenoxy]-2-propanol
l-isopropylamino-3-(4-tosyloksyetylfenoksy)-2-propanol-hydroklorid, fremstilt ifølge eksempel 1, punkt b), oppløses i metanol. Den erholdte oppløsning gjøres sur med hydrogen-kloridgass og kokes i 20 timer. Metanolen avdampes, og residuet oppløses i vann. Vannoppløsningen vaskes med toluen og gjøres alkalisk med natriumhydroksyd. Produktet ekstraheres med kloroform, tørkes med natriumsulfat, og kloroformen avdampes. Residuet er metoprolol-base, som overføres i tartrat i vinsur aceton. Det erholdte metoprolol-tartratets smeltepunkt er ca. 120°C 1-isopropylamino-3-(4-tosyloxyethylphenoxy)-2-propanol hydrochloride, prepared according to example 1, point b), is dissolved in methanol. The resulting solution is acidified with hydrogen chloride gas and boiled for 20 hours. The methanol is evaporated, and the residue is dissolved in water. The aqueous solution is washed with toluene and made alkaline with sodium hydroxide. The product is extracted with chloroform, dried with sodium sulfate, and the chloroform is evaporated. The residue is metoprolol base, which is transferred into tartrate in tartaric acetone. The melting point of the obtained metoprolol tartrate is approx. 120°C
Claims (7)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI783646A FI58909C (en) | 1978-11-29 | 1978-11-29 | REFERENCE FOR THERAPEUTIC ACTIVATION OF THERAPEUTIC ACTIVATING OF 1-ISOPROPYLAMINO-3- (4- (2-METHOXYETHYL) -PHENOXY) -2-PROPANOL OCH DESS SYRAADDITIONSSALTER |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO793871L true NO793871L (en) | 1980-05-30 |
Family
ID=8512188
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO793871A NO793871L (en) | 1978-11-29 | 1979-11-28 | METHOD OF PREPARING METOPROL. |
Country Status (5)
| Country | Link |
|---|---|
| DK (1) | DK154072C (en) |
| FI (1) | FI58909C (en) |
| NL (1) | NL7908669A (en) |
| NO (1) | NO793871L (en) |
| SE (1) | SE443779B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101665441B (en) * | 2009-09-18 | 2013-04-10 | 安徽省庆云医药化工有限公司 | Method for preparing l-betaxolol hydrochloride |
| CN102381995B (en) * | 2010-08-31 | 2015-04-15 | 扬子江药业集团北京海燕药业有限公司 | Preparation method of metoprolol |
-
1978
- 1978-11-29 FI FI783646A patent/FI58909C/en not_active IP Right Cessation
-
1979
- 1979-11-28 SE SE7909816A patent/SE443779B/en not_active IP Right Cessation
- 1979-11-28 NO NO793871A patent/NO793871L/en unknown
- 1979-11-28 DK DK504879A patent/DK154072C/en not_active IP Right Cessation
- 1979-11-29 NL NL7908669A patent/NL7908669A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FI58909B (en) | 1981-01-30 |
| FI58909C (en) | 1981-05-11 |
| NL7908669A (en) | 1980-06-02 |
| SE443779B (en) | 1986-03-10 |
| DK154072C (en) | 1989-03-06 |
| FI783646A (en) | 1980-05-30 |
| DK504879A (en) | 1980-05-30 |
| SE7909816L (en) | 1980-05-30 |
| DK154072B (en) | 1988-10-10 |
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