NO145402B - PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE PROPANOLAMINE, METOPROLOL - Google Patents
PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE PROPANOLAMINE, METOPROLOL Download PDFInfo
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- NO145402B NO145402B NO790825A NO790825A NO145402B NO 145402 B NO145402 B NO 145402B NO 790825 A NO790825 A NO 790825A NO 790825 A NO790825 A NO 790825A NO 145402 B NO145402 B NO 145402B
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- Prior art keywords
- metoprolol
- propanol
- phenoxy
- acid
- preparation
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 20
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 title claims description 15
- 229960002237 metoprolol Drugs 0.000 title description 12
- 238000002360 preparation method Methods 0.000 title description 6
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 29
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 22
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 16
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 238000007796 conventional method Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims 2
- CLTYDMIYCODWLE-UHFFFAOYSA-N 1-[4-(3-chloro-2-hydroxypropoxy)phenyl]-2-methoxyethanone Chemical compound ClCC(COC1=CC=C(C=C1)C(=O)COC)O CLTYDMIYCODWLE-UHFFFAOYSA-N 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 229940098779 methanesulfonic acid Drugs 0.000 description 9
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CYGMBGZUOIIVSF-UHFFFAOYSA-N 1-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]-2-methoxyethanone Chemical compound COCC(=O)C1=CC=C(OCC(O)CNC(C)C)C=C1 CYGMBGZUOIIVSF-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- 150000008062 acetophenones Chemical class 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 description 2
- 239000013067 intermediate product Substances 0.000 description 2
- -1 methylene compound Chemical class 0.000 description 2
- 239000003087 receptor blocking agent Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YRNDGUSDBCARGC-UHFFFAOYSA-N 2-methoxyacetophenone Chemical compound COCC(=O)C1=CC=CC=C1 YRNDGUSDBCARGC-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 150000008366 benzophenones Chemical class 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229940030602 cardiac therapy drug Drugs 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000003670 easy-to-clean Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000005194 ethylbenzenes Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 229960001300 metoprolol tartrate Drugs 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical group CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 150000003152 propanolamines Chemical class 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 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
- 239000012485 toluene extract Substances 0.000 description 1
Classifications
-
- 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
- C07C217/32—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 the six-membered aromatic ring or condensed ring system containing that ring being further substituted
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
- C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
- C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Foreliggende oppfinnelse angår en ny fremgangsmåte The present invention relates to a new method
for fremstilling av l-isopropylamino-3-[4-(2-metoksyetyl)fenoksy]-2-propanol eller metoprolol med formelen for the preparation of l-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]-2-propanol or metoprolol with the formula
Metropolol er et såkalt 3-reseptorblokkerende middel. De fleste 3-reseptorblokkerende midler har den ulempe at de ikke bare blokkerer hjertets 3-reseptorer, men også 3_reseptorene i blodkar og lunger, hvilket er en ulempe ved behandling av astma-pasienter; Metoprolol har ikke denne bivirkning og er derfor et viktig legemiddel innen hjerteterapien. Metropolol is a so-called 3-receptor blocking agent. Most 3-receptor blocking agents have the disadvantage that they not only block the 3-receptors of the heart, but also the 3-receptors in blood vessels and lungs, which is a disadvantage in the treatment of asthma patients; Metoprolol does not have this side effect and is therefore an important drug in cardiac therapy.
Fremstillingen av metoprolol er kjent, f.eks. fra svensk patent nr. 354 851, der 12 analogifremgangsmåter for dens fremstilling er beskrevet. Felles for disse metoder er at de alle angår fremstillingen av propanolsidekjeden. The preparation of metoprolol is known, e.g. from Swedish patent no. 354 851, where 12 analogous methods for its production are described. What these methods have in common is that they all concern the preparation of the propanol side chain.
Ifølge foreliggende oppfinnelse fremstilles metoprolol via andre mellomprodukter, og fremgangsmåten karakteriseres ved at man i propanolaminderivatet med formelen According to the present invention, metoprolol is produced via other intermediates, and the method is characterized by the fact that in the propanolamine derivative with the formula
reduserer karbonylgruppen i fenylgruppens 4-substituent til en metylengruppe med natriumborhydrid. Reduksjonen utføres i nærvær av sterkt sure reagenser, nemlig trifluoreddiksyre, metan- eller p-toluensulfonsyre, idet reaksjonen går via et karbokation (III). reduces the carbonyl group in the phenyl group's 4-substituent to a methylene group with sodium borohydride. The reduction is carried out in the presence of strongly acidic reagents, namely trifluoroacetic acid, methane- or p-toluenesulfonic acid, as the reaction proceeds via a carbocation (III).
I finsk patentansøkning 76 2507 er beskrevet at ovennevnte mellomprodukt II kan reduseres til metoprolol. I denne ansøk-ning fremstilles imidlertid mellomproduktet ved andre fremgangsmåter, og reduksjonen utføres ved katalytisk hydrogenering under helt andre betingelser. In Finnish patent application 76 2507, it is described that the above-mentioned intermediate II can be reduced to metoprolol. In this application, however, the intermediate product is prepared by other methods, and the reduction is carried out by catalytic hydrogenation under completely different conditions.
Fremgangsmåten ifølge foreliggende oppfinnelse kan be-skrives ved hjelp av følgende formelskjerna: The method according to the present invention can be described using the following core formula:
De to første trinn utføres ved anvendelse av konvensjonelle metoder. Reduksjonen av karbonylgruppen med natriumborhydrid til en metylengruppe er likeledes i og for seg en kjent reaksjon, men den er tidligere ikke anvendt for fremstilling av forbindelser av denne type. Anvendelse av reaksjonen er f.eks. beskrevet i Fieser & Fieser-, Reagents for Organic Synthesis, John Wiley and Sons; vol. 1 (1967), s. 1050, vol. 3 (1972), s.263, vol. 4 (1974) s.209. Reaksjonen utføres vanligvis i vannholdige oppløsningsmidler og den leder oftest til dannelse av en alkohol, men avhengig av forbindelsene og betingelsene kan den også lede til tilsvarende metylenforbindelse. The first two steps are carried out using conventional methods. The reduction of the carbonyl group with sodium borohydride to a methylene group is likewise a known reaction in and of itself, but it has not previously been used for the preparation of compounds of this type. Application of the reaction is e.g. described in Fieser & Fieser-, Reagents for Organic Synthesis, John Wiley and Sons; Vol. 1 (1967), p. 1050, vol. 3 (1972), p.263, vol. 4 (1974) p.209. The reaction is usually carried out in aqueous solvents and it most often leads to the formation of an alcohol, but depending on the compounds and the conditions it can also lead to the corresponding methylene compound.
Ifølge ovennevnte litteraturhenvisning, vol. 3, s. 263, reagerer acetofenon, som er substituert i 2- og 4-stilling med fenoliske hydroksyler, med natriumborhydrid i kokende alkalisk vannoppløsning til tilsvarende etylebenzenderivat. Når man lar mellomproduktet II reagere under tilsvarende forhold, skjer reaksjonen ikke på ønsket måte. According to the above literature reference, vol. 3, p. 263, acetophenone, which is substituted in the 2- and 4-position with phenolic hydroxyls, reacts with sodium borohydride in boiling alkaline water solution to the corresponding ethylbenzene derivative. When the intermediate II is allowed to react under similar conditions, the reaction does not take place in the desired way.
Ifølge oppfinnelsen lykkes derimot reaksjonen uventet According to the invention, however, the reaction succeeds unexpectedly
i trifluoreddiksyre samt i et inert oppløsningsmiddel i nærvær av metansulfonsyre eller p-toluensulfonsyre. in trifluoroacetic acid as well as in an inert solvent in the presence of methanesulfonic acid or p-toluenesulfonic acid.
Ifølge publikasjonen G. W. Gribble, R. M. Leese, Synthesis 1977, 172-176 er det kjent at en ketogruppe kan reduseres med NaBH^ til en metylengruppe i trifluoreddiksyre, idet reaksjonen går via et karbokation. Reduksjonen lykkes imidlertid tilfreds-stillende bare med benzofenonderivater, som har et godt stabili-sert karbokation, men ikke med acetofenonderivater, som som hoved-produkt gir dimeriseringsprodukter. Derimot er det kjent at acetofenonderivater kan reduseres i.trifluoreddiksyre med trialkylsila-ner (J.Org.Chem. 38(1973)2675). Det er derfor overraskende at reduksjonen i trifluoreddiksyre ved de betingelser som anvendes i. henhold til foreliggende oppfinnelse, lykkes og går med.så godt . utbytte. According to the publication G. W. Gribble, R. M. Leese, Synthesis 1977, 172-176, it is known that a keto group can be reduced with NaBH^ to a methylene group in trifluoroacetic acid, the reaction proceeding via a carbocation. However, the reduction only succeeds satisfactorily with benzophenone derivatives, which have a well-stabilized carbocation, but not with acetophenone derivatives, which give dimerization products as the main product. In contrast, it is known that acetophenone derivatives can be reduced in trifluoroacetic acid with trialkylsilanes (J.Org.Chem. 38(1973)2675). It is therefore surprising that the reduction in trifluoroacetic acid under the conditions used in accordance with the present invention is successful and goes so well. dividend.
Ved ytterligere undersøkelser er det funnet at reaksjonen også lykkes ved anvendelse av billige organiske syrer så som metansulf onsyre og p-toluensulf onsyre.. Dette er forsåvidt overraskende i og med at karbokationer ikke tidligere er fremstilt ved hjelp av sulfonsyrederivater. In further investigations, it has been found that the reaction is also successful when cheap organic acids such as methanesulfonic acid and p-toluenesulfonic acid are used. This is certainly surprising as carbocations have not previously been prepared using sulfonic acid derivatives.
Av de sistnevnte reagenser er spesielt metansulfonsyre meget fordelaktigere enn trifluoreddiksyre. For det første er metansulfonsyre betydelig billigere, dens pris er ca. 25 % av prisen på trifluoreddiksyre. Ved anvendelse av metansulfonsyre kan man også klare seg med mindre mengder NaBH^, ca. 1/3. Til tross for dette er utbyttet av samme størrelsesorden som ved anvendelse av trifluoreddiksyre. Dessuten er metansulfonsyre lukt-løs og er derfor lettere håndterbar enn trifluoreddiksyre som har en stikkende lukt. p-toluensulfonsyre er enda billigere enn metansulfonsyre, dens pris er ca. 6 % av prisen på trifluoreddiksyre. Of the latter reagents, methanesulfonic acid in particular is much more advantageous than trifluoroacetic acid. Firstly, methanesulfonic acid is significantly cheaper, its price is approx. 25% of the price of trifluoroacetic acid. When using methanesulphonic acid, you can also get by with smaller amounts of NaBH^, approx. 1/3. Despite this, the yield is of the same order of magnitude as when using trifluoroacetic acid. Moreover, methanesulfonic acid is odorless and is therefore easier to handle than trifluoroacetic acid, which has a pungent smell. p-toluenesulfonic acid is even cheaper than methanesulfonic acid, its price is approx. 6% of the price of trifluoroacetic acid.
Ved en sammenligning av fremgangsmåten ifølge oppfinnelsen med fremgangsmåten ifølge finsk ansøkning 762 507, kan det for det første konstanteres at mellomproduktet II i den finske ansøkningen 762 507 er fremstilt via ketalen (IV). Ifølge foreliggende oppfinnelse går man direkte ut fra tilsvarende keton. In a comparison of the method according to the invention with the method according to Finnish application 762 507, it can first be ascertained that the intermediate II in the Finnish application 762 507 is produced via the ketal (IV). According to the present invention, one proceeds directly from the corresponding ketone.
Fremgangsmåten er derfor to trinn kortere ved at fremstillingen av ketalen og hydrolysetrinnet faller bort. Det gjenværende re-duksjonstrinn er i finsk ansøkning 76 2507 en katalytisk hydrogenering der det ikke forekommer noe karbokation-mellomprodukt. Det kan derfor betraktes som en reaksjonsmekanisk annen.fremgangsmåte. The procedure is therefore two steps shorter in that the preparation of the ketal and the hydrolysis step are omitted. The remaining reduction step is in Finnish application 76 2507 a catalytic hydrogenation in which no carbocation intermediate occurs. It can therefore be considered a reaction-mechanistic alternative method.
I eksempel 1 i finsk ansøkning 76 2507 fårman hydroklori-det av mellomproduktet II i et utbytte på 45,3 %. Ved fremgangsmåten ifølge oppfinnelsen får man mellomproduktet i et utbytte på 75 %. Likeledes er utbyttene ved reduksjonstrinnet av helt for-skjellige klasser. I finsk ansøkning 76 2507 gir den katalytiske hydrogeneringen 53,4 % metoprolol-tartrat, mens reduksjonen NaBH4/CF3COOH gir et utbytte på 91,0 % og NaBH4/CH3S03H 85 % av metoprolol-base. Disse høye utbytter gir et merkbart bedre øko-nomisk sluttresultatefter som mellomproduktet II er resultatet av en lang reaksjonsserie, som i finsk ansøkning 76 2507 består av 7 trinn og i foreliggende ansøkning 5 trinn. In example 1 in Finnish application 76 2507, the hydrochloride of intermediate II is obtained in a yield of 45.3%. With the method according to the invention, the intermediate product is obtained in a yield of 75%. Likewise, the yields at the reduction stage are of completely different classes. In Finnish application 76 2507, the catalytic hydrogenation gives 53.4% of metoprolol tartrate, while the reduction NaBH4/CF3COOH gives a yield of 91.0% and NaBH4/CH3SO3H 85% of metoprolol base. These high yields give a noticeably better economic final result as the intermediate II is the result of a long reaction series, which in Finnish application 76 2507 consists of 7 steps and in the present application 5 steps.
Ved en sammenligning av metodenes lønnsomhet bør det ytterligere tas i betraktning at en katalytisk hydrogenering er teknisk vanskeligere å beherske og en farlig prosess. Dessuten er den anvendte katalysatormengde høy. Ved fremgangsmåten ifølge oppfinnelsen utføres reaksjonen helt enkelt ved omrøring ved 0°C av ufarlige stoffer. When comparing the profitability of the methods, it should also be taken into account that a catalytic hydrogenation is technically more difficult to master and a dangerous process. In addition, the amount of catalyst used is high. In the method according to the invention, the reaction is carried out simply by stirring harmless substances at 0°C.
Mellomproduktet I får man ved oppvarmning av 4-hydroksy-M>-nietoksyacetofenon i et overskudd av epiklorhydrin med anvendelse av trietylamin som katalysator. Syntesen går praktisk talt kvantitativt. Intermediate I is obtained by heating 4-hydroxy-N>-nietoxyacetophenone in an excess of epichlorohydrin using triethylamine as catalyst. The synthesis is practically quantitative.
Mellomproduktet II fremstilles ved at mellomproduktet I, et overskudd av isopropylamin og en lavere alkohol oppvarmes til kokning. Intermediate II is prepared by heating intermediate I, an excess of isopropylamine and a lower alcohol to boiling.
I det siste trinn omsettes mellomproduktet II med natriumborhydrid ved lav temperatur, ca. 0°C, i trifluoreddiksyre eller i et inert oppløsningsmiddel inneholdende metansulfonsyre eller p-toluensulfonsyre. Ved anvendelse av trifluoreddiksyre fungerer denne både som reaksjonskomponent og oppløsningsmiddel. Syren anvendes i overskudd som efter reaksjonen lett kan regenereres ved destillasjon. Når reduksjonen utføres i nærvær av metansulfonsyre eller p-toluensulfonsyre, anvendes som oppløsningsmiddel et inert organisk oppløsningsmiddel, f.eks. metylenklorid. I det siste trinn får man metoprolol med godt utbytte i en form som er lett å rense. In the last step, the intermediate II is reacted with sodium borohydride at a low temperature, approx. 0°C, in trifluoroacetic acid or in an inert solvent containing methanesulfonic acid or p-toluenesulfonic acid. When trifluoroacetic acid is used, this acts as both a reaction component and a solvent. The acid is used in excess, which after the reaction can easily be regenerated by distillation. When the reduction is carried out in the presence of methanesulfonic acid or p-toluenesulfonic acid, an inert organic solvent, e.g. methylene chloride. In the last step, metoprolol is obtained with a good yield in a form that is easy to clean.
Fremgangsmåten ifølge oppfinnelsen er således både øko-nomisk og lett gjennomførbar i teknisk skala. Den er derfor en god løsning for fremstillingen av metoprolol. The method according to the invention is thus both economical and easily implementable on a technical scale. It is therefore a good solution for the production of metoprolol.
Oppfinnelsen belyses nærmere ved følgende eksempler: The invention is explained in more detail by the following examples:
Eksempel 1 Example 1
l-klor-3-[-(4metoksymetylkarbonyl)fenoksy]-3-propanol 1-chloro-3-[-(4-methoxymethylcarbonyl)phenoxy]-3-propanol
7,5 g 4-hydroksy-u>metoksyacetofenon, 40 ml epiklorhydrin og 0,2 ml trietylamin oppvarmes i ca. 5 timer til en temperatur på 100-120°C. Overskudd av epiklorhydrin avdestilleres i vakuum. Derved får man et oljeaktig residuum, 11,7 g (100 %), som uten å renses anvendes i eksempel 2. Den rensede forbindel-ses IR-spektrum er avbildet på fig. 1. 7.5 g of 4-hydroxy-u>methoxyacetophenone, 40 ml of epichlorohydrin and 0.2 ml of triethylamine are heated for approx. 5 hours at a temperature of 100-120°C. Excess epichlorohydrin is distilled off in a vacuum. This gives an oily residue, 11.7 g (100%), which is used without purification in example 2. The IR spectrum of the purified compound is shown in fig. 1.
Eksempel 2 l-isopropylamino-3-[4-(metoksymetylkarbonyl)fenoksy]-2-propanol 11,7 g av produktet fra foregående eksempel, 20 ml metanol og 20 ml isopropylamin kokes under tilbakeløpskjøling i 6 timer. Oppløsningsmidlet avdestilleres og residuet oppløses i 10 prosentig eddiksyre. Oppløsningen vaskes med toluen og gjø-res alkalisk med natriumhydroksydoppløsning. Den dannede olje ekstraheres med toluen og toluenen avdestilleres i vakuum. Residuet omkrystalliseres i f.eks. di-isopropyleter, hvorved man får 9,5 g farveløse krystaller, smp. 87-90°C (75 %). Stoffets IR-spektrum fremgår av fig. 2. Example 2 1-isopropylamino-3-[4-(methoxymethylcarbonyl)phenoxy]-2-propanol 11.7 g of the product from the previous example, 20 ml of methanol and 20 ml of isopropylamine are boiled under reflux for 6 hours. The solvent is distilled off and the residue is dissolved in 10 per cent acetic acid. The solution is washed with toluene and made alkaline with sodium hydroxide solution. The oil formed is extracted with toluene and the toluene is distilled off in a vacuum. The residue is recrystallized in e.g. di-isopropyl ether, whereby 9.5 g of colorless crystals are obtained, m.p. 87-90°C (75%). The substance's IR spectrum appears in fig. 2.
Eksempel 3 Example 3
1- isopropylamino-3-[4-(2-metoksyetyl)fenoksy]-2-propanol 1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]-2-propanol
140 ml trifluoreddiksyre avkjøles til 0°C og derefter tilføres gradvis ved 0°C en blanding som inneholder 9,5 g av den i eksempel 2 erholdte ketoforbindelse og 19 g natriumborhydrid. Efter ca. 1 time tilføres vann, og pH reguleres til ca. 10 med natriumhydroksydoppløsning. Produktet ekstraheres med f.eks. toluen, toluenekstrakten vaskes med vann, tørkes med natriumkarbonat og inndampes til tørrhet. Residuet omkrystalliseres fra f.eks. heptan, hvorved man får 8,2 g farveløs metoproplol, smeltepunkt 45°C (91 %). Når forbindelsen ved vanlige metoder over-føres til hydroklorid, fåes krystaller med smeltepunkt 83°C. 140 ml of trifluoroacetic acid is cooled to 0°C and then a mixture containing 9.5 g of the keto compound obtained in example 2 and 19 g of sodium borohydride is added gradually at 0°C. After approx. Water is added for 1 hour, and the pH is adjusted to approx. 10 with sodium hydroxide solution. The product is extracted with e.g. toluene, the toluene extract is washed with water, dried with sodium carbonate and evaporated to dryness. The residue is recrystallized from e.g. heptane, which gives 8.2 g of colorless metoprolol, melting point 45°C (91%). When the compound is converted to hydrochloride by usual methods, crystals with a melting point of 83°C are obtained.
Eksempel 4 Example 4
250 ml metylenklorid og 50 ml metansulfonsyre avkjøles 250 ml of methylene chloride and 50 ml of methanesulfonic acid are cooled
til 0°C. Ved denne temperatur tilføres gradvis en blanding, be-stående av 10 g l-isopropylamino-3-[4-(metoksymetylkarbonyl)fenoksy]-2- propanol og 5 g natriumborhydrid. Blandingen omrøres 1 time ved 0°C, hvorefter temperaturen får stige til romtemperatur. to 0°C. At this temperature, a mixture consisting of 10 g of 1-isopropylamino-3-[4-(methoxymethylcarbonyl)phenoxy]-2-propanol and 5 g of sodium borohydride is gradually added. The mixture is stirred for 1 hour at 0°C, after which the temperature is allowed to rise to room temperature.
Vann tilføres og pH reguleres til ca. 10 med natriumhydroksyd-oppløsning. Metylenkloridfasen fraskilles, vaskes med vann, Water is added and the pH is adjusted to approx. 10 with sodium hydroxide solution. The methylene chloride phase is separated, washed with water,
tørkes med natriumkarbonat og inndampes til tørrhet. Residuet omkrystalliseres fra f.eks. heptan. Derved får man 8,1 g (85 %) farveløs metoprolol, smeltepunkt 45°C. Når forbindelsen ved vanlige metoder overføres til hydroklorid, fåes krystaller med smeltepunkt 83°C. Tilsvarende tartrat har smeltepunkt 118-120°C. dried with sodium carbonate and evaporated to dryness. The residue is recrystallized from e.g. heptane. This gives 8.1 g (85%) of colorless metoprolol, melting point 45°C. When the compound is transferred to hydrochloride by usual methods, crystals with a melting point of 83°C are obtained. Corresponding tartrate has a melting point of 118-120°C.
Eksempel 5 Example 5
150 g tørr p-toluensulfonsyre og 400 ml metylenklorid avkjøles til 0°C. Derefter tilføres en blanding av 10 g l-iso-propylamino-3- [4-('metoksymetylkarbonyl) fenoksy] -2-propanol og 20 g natriumborhydrid ved 0°C, og man fortsetter som i eksempel 4. Man fr 5,0 g (52,6 %) metoprolol, smeltepunkt 45°C. 150 g of dry p-toluenesulfonic acid and 400 ml of methylene chloride are cooled to 0°C. A mixture of 10 g of 1-iso-propylamino-3-[4-('methoxymethylcarbonyl)phenoxy]-2-propanol and 20 g of sodium borohydride is then added at 0°C, and the procedure is continued as in example 4. Man fr 5.0 g (52.6%) metoprolol, melting point 45°C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI781001A FI59392C (en) | 1978-04-01 | 1978-04-01 | PROFESSIONAL PROTECTION FOR THERAPEUTIC ACTIVATION 1-ISOPROPYLAMINO-3- (4- (2-METHOXYTHYL) PHENOXY) -2-PROPANOL SAMT DESS SYRAADDITIONSSALTER |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO790825L NO790825L (en) | 1979-10-02 |
| NO145402B true NO145402B (en) | 1981-12-07 |
| NO145402C NO145402C (en) | 1982-03-17 |
Family
ID=8511594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO790825A NO145402C (en) | 1978-04-01 | 1979-03-12 | PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE PROPANOLAMINE, METOPROLOL |
Country Status (8)
| Country | Link |
|---|---|
| JP (1) | JPS54145623A (en) |
| AT (1) | AT364349B (en) |
| CH (1) | CH639065A5 (en) |
| DK (1) | DK145195C (en) |
| FI (1) | FI59392C (en) |
| NL (1) | NL7902407A (en) |
| NO (1) | NO145402C (en) |
| SE (1) | SE444677B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FI59985C (en) * | 1980-05-26 | 1982-01-08 | Farmos Oy | PROFESSIONAL PROTECTION FOR THERAPEUTIC ACTIVATION 1-ISOPROPYLAMINO-3- (4- (2-METHOXYTHYL) PHENOXY) -2-PROPANOL SAMT DESS SYRA ADDITIONAL SALT |
-
1978
- 1978-04-01 FI FI781001A patent/FI59392C/en not_active IP Right Cessation
-
1979
- 1979-03-12 NO NO790825A patent/NO145402C/en unknown
- 1979-03-15 AT AT0196479A patent/AT364349B/en not_active IP Right Cessation
- 1979-03-28 NL NL7902407A patent/NL7902407A/en not_active Application Discontinuation
- 1979-03-29 SE SE7902821A patent/SE444677B/en not_active IP Right Cessation
- 1979-03-30 CH CH301279A patent/CH639065A5/en not_active IP Right Cessation
- 1979-03-30 DK DK131079A patent/DK145195C/en not_active IP Right Cessation
- 1979-03-30 JP JP3923679A patent/JPS54145623A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| NL7902407A (en) | 1979-10-03 |
| DK145195C (en) | 1983-04-05 |
| JPS54145623A (en) | 1979-11-14 |
| SE444677B (en) | 1986-04-28 |
| SE7902821L (en) | 1979-10-02 |
| ATA196479A (en) | 1981-03-15 |
| FI59392C (en) | 1982-02-02 |
| CH639065A5 (en) | 1983-10-31 |
| AT364349B (en) | 1981-10-12 |
| FI781001A (en) | 1979-10-02 |
| FI59392B (en) | 1981-04-30 |
| NO790825L (en) | 1979-10-02 |
| JPS6130653B2 (en) | 1986-07-15 |
| NO145402C (en) | 1982-03-17 |
| DK131079A (en) | 1979-10-02 |
| DK145195B (en) | 1982-10-04 |
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