FI59392C - PROFESSIONAL PROTECTION FOR THERAPEUTIC ACTIVATION 1-ISOPROPYLAMINO-3- (4- (2-METHOXYTHYL) PHENOXY) -2-PROPANOL SAMT DESS SYRAADDITIONSSALTER - Google Patents
PROFESSIONAL PROTECTION FOR THERAPEUTIC ACTIVATION 1-ISOPROPYLAMINO-3- (4- (2-METHOXYTHYL) PHENOXY) -2-PROPANOL SAMT DESS SYRAADDITIONSSALTER Download PDFInfo
- Publication number
- FI59392C FI59392C FI781001A FI781001A FI59392C FI 59392 C FI59392 C FI 59392C FI 781001 A FI781001 A FI 781001A FI 781001 A FI781001 A FI 781001A FI 59392 C FI59392 C FI 59392C
- Authority
- FI
- Finland
- Prior art keywords
- propanol
- phenoxy
- isopropylamino
- acid
- methoxythyl
- Prior art date
Links
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 title description 3
- 101100148710 Clarkia breweri SAMT gene Proteins 0.000 title 1
- 230000004913 activation Effects 0.000 title 1
- KHUXNRRPPZOJPT-UHFFFAOYSA-N phenoxy radical Chemical class O=C1C=C[CH]C=C1 KHUXNRRPPZOJPT-UHFFFAOYSA-N 0.000 title 1
- 230000001225 therapeutic effect Effects 0.000 title 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 23
- 238000000034 method Methods 0.000 claims description 23
- 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 14
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 11
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 claims description 11
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 10
- 239000012279 sodium borohydride Substances 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 6
- 239000012442 inert solvent Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 3
- 238000007796 conventional method Methods 0.000 claims 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- 229960002237 metoprolol Drugs 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 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
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical group CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 150000008062 acetophenones Chemical class 0.000 description 2
- 239000002876 beta blocker Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 235000014121 butter Nutrition 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 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 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 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
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 150000008366 benzophenones Chemical class 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000005194 ethylbenzenes Chemical class 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- -1 methylene compound Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000009965 odorless effect Effects 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
- 239000002994 raw material Substances 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 description 1
- 229940095064 tartrate Drugs 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
Landscapes
- 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
@ SUOMI—FINLAND patenttijulkaisu—patentskrift 59392 (g) Kv.lk?/lnt.CI.3 CT 0? C 93/06 ® @ Patenttihakemus — Patentansökning γβΙΟΟΙ @ Hakemispäivä — Ansöknlngsdag 01.Oh.78 tjioO @ Alkupäivä —Glltlghetsdag 01.04.78 @ Tullut Julkiseksi — Bllvlt offentlig 02.10.79 @ Nähtäväksi panon Ja kuul.Julkalsun pvm.—@ FINNISH — FINLAND patent publication — patent patent 59392 (g) Kv.lk?/lnt.CI.3 CT 0? C 93/06 ® @ Patent application - Patentansökning γβΙΟΟΙ @ Application date - Ansöknlngsdag 01.Oh.78 tjioO @ Start date —Glltlghetsdag 01.04.78 @ Become public - Bllvlt offentlig 02.10.79 @ Date of publication and publication.
Ansökan utlagd och utl.skriften publicerad 30.0U.8lAnsökan utlagd och utl.skriften publicerad 30.0U.8l
Patentti- ja rekisterihallitus © Patentti myönnetty —Patent meddelat 02.02.82National Board of Patents and Registration © Patent granted —Patent meddelat 02.02.82
Patent- och registerstyrelsen @ (33)(31) Pyydetty etuoikeus — Begärd priorltet (73) AB Hassle, S-U31 83 Mölndal, Ruotsi-Sverige(SE) (72) Soini Kanerva Huhta, Kempele, Lasse Antero Koskenniska, Oulu,Patent- och registerstyrelsen @ (33) (31) Privilege claimed - Begärd priorltet (73) AB Hassle, S-U31 83 Mölndal, Sweden-Sweden (SE) (72) Soini Kanerva Huhta, Kempele, Lasse Antero Koskenniska, Oulu,
Suomi-Finland(FI) (7U) Berggren Oy Ab (5U) Menetelmä terapeuttisesti aktiivisen l-isopropyyliamino-3“A~(2-metoksi-etyyli)fenoksi7-2-propanolin ja sen happoadditiosuolojen valmistamiseksi - Förfarande för framställning av terapeutiskt aktiv l-isopropylamino-3--/U-(2-metoxietyl)fenoxi7-2-propanol samt dess syraadditionssalterSuomi-Finland (FI) (7U) Berggren Oy Ab (5U) Method for the preparation of therapeutically active 1-isopropylamino-3 'N- (2-methoxyethyl) phenoxy] -2-propanol and its acid addition salts - Förfarande för framställning av terapeutiskt Aktiv l -isopropylamino-3- [N- (2-methoxyethyl) phenoxy] -2-propanol
Keksinnön kohteena on uusi meneteinä valmistaa l-ieopropyyli-amino-3-[4-(2-metoksietyyli)fenoksi]-2-propanolia eli metoprolo-lia, jonka kaava on 0^0-0^-(^^-1^-^The present invention relates to a new process for the preparation of 1-leopropylamino-3- [4- (2-methoxyethyl) phenoxy] -2-propanol, i.e. metoprolol, of the formula O ^
Metoprololi on ns. β-reseptorisalpausaine. Useimmilla |3-salpaa-jilla on haittapuolena se, että ne eivät salpaa ainoastaan sydämen 0-reseptoreja, vaan myös β-reseptoreja verisuonissa ja keuhkoissa, mikä on epäkohta astamapotllaiden hoidossa. Metoprolo-lilla ei ole tätä sivuvaikutusta, ja siten se on tärkeä lääkeaine sydänsairauksien hoidossa.Metoprolol is a so-called β-receptor blocking agent. The disadvantage of most β-blockers is that they block not only cardiac O-receptors but also β-receptors in the 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 the treatment of heart disease.
Metoprololin valmistus on tunnettu esimerkiksi ruotsalaisesta patentista n:o 354 851, jossa kuvataan 12 analoglamenetelmää sen valmistamiseksi· Näille menetelmille on yhteistä se, että ne kaikki kohdistuvat propanolisivuketjun valmistukseen.The preparation of metoprolol is known, for example, from Swedish Patent No. 354,851, which describes 12 analogous methods for its preparation. · These methods have in common that they all concern the preparation of the propanol side chain.
2 593922 59392
Keksinnön kohteena on menetelmä valmistaa metoprololia pelkistämällä propanoliamiinijohdannaisessa, jonka kaava onThe present invention relates to a process for the preparation of metoprolol by reduction in a propanolamine derivative of the formula
/——y OH/ —— y OH
CH30-CH2-C0-/£) \ 0-CH2-i:H-CH2-NH-CH( CH3 ) 2 (II) bentseenirenkaan 4-asemassa olevan substituentin karbonyyliryhmä natriumboorihydridillä metyleeniryhmäksi. Menetelmälle on tunnusomaista, että pelkistys suoritetaan inertissä liuottimessa lämpötilan ollessa n. 0°C metaanisulfonihapon tai p-tolueeni-sulfonihapon läsnäollessa.CH30-CH2-CO- (E) -O-CH2-i: the carbonyl group of the substituent in the 4-position of the H-CH2-NH-CH (CH3) 2 (II) benzene ring with sodium borohydride to the methylene group. The process is characterized in that the reduction is carried out in an inert solvent at a temperature of about 0 ° C in the presence of methanesulfonic acid or p-toluenesulfonic acid.
Kaavoin kuvattuna keksinnön mukainen menetelmä on seuraava:Schematically illustrated, the method of the invention is as follows:
J-V j)H NaBH4/CH3S03HJ-V j) H NaBH4 / CH3SO3H
CHjO-C^-CO-/ Q V-0-CH2-CH-CH2-NH-CH(CH3)2-->CH 2 O-CH 2 -CO- / QV-O-CH 2 -CH-CH 2 -NH-CH (CH 3) 2 ->
'-' tai CH j<Ö)- S03H'-' or CH 2 (SO) - SO 3 H
(II) inertti liuotin(II) inert solvent
© t-V OH© t-V OH
ch3o-ch2-ch-( Q V-o-ch2-ch-ch2-nh-ch(ch3)2--v> L (lii) CH30-CH2cH 0-CH2-CH-CH2-NH-CH(ch3)2ch3o-ch2-ch- (QV-o-ch2-ch-ch2-nh-ch (ch3) 2 - v> L (lii) CH3O-CH2cHO-CH2-CH-CH2-NH-CH (ch3) 2
Siten keksinnön mukaisessa menetelmässä karbonyyliryhmä pelkistetään natriumboorihydridillä voimakkaasti happamissa olosuhteissa käyttäen happona metaanisulfonihappoa tai p-tolueeni-sulfonihappoa, karbokationin (III) kautta metyleeniryhmäksi.Thus, in the process of the invention, the carbonyl group is reduced with sodium borohydride under strongly acidic conditions using methanesulfonic acid or p-toluenesulfonic acid as the acid, via the carbocation cation (III) to the methylene group.
Suomalaisesta hakemuksesta n:o 762 507, sekä hakemuksestamme n:o 773 391 on tunnettua, että yllä mainittu kaavan II mukainen yhdiste voidaan pelkistää metoprololiksl. Nyt esitetty pelkis-tysmenetelmä eroaa hakemuksen n:o 762 507 menetelmästä siinä, että se suoritetaan natriumboorihydridillä, kun taas hakemuksessa n:o 762 507 pelkistys on katalyyttinen. Olosuhteet ovat lisäksi täysin erilaiset.It is known from Finnish application No. 762,507 and from our application No. 773,391 that the above-mentioned compound of formula II can be reduced to metoprololic acid. The reduction process now presented differs from the process of application No. 762,507 in that it is performed with sodium borohydride, whereas in application No. 762,507 the reduction is catalytic. In addition, the circumstances are completely different.
- 3 - 59392- 3 - 59392
Ketoryhmän pelkistys natriumboorihydridillä metyleeniryhmäksi on sinänsä tunnettu reaktio. Sovellutuksia reaktiosta voidaan löytää esimerkiksi kirjasta Fieser & Fieser; Reagents for Organic Synthesis, John Wiley and Sons, voi. 1 (1967), sivu 1050; voi. 3 (1972), sivu 263; voi. 4 (1974), sivu 209. Reaktio suoritetaan yleensä vesipitoisissa liuottimissa, ja se johtaa useimmiten alkoholiin, mutta yhdisteistä ja olosuhteista riippuen se voi myös johtaa vastaavaan metyleeniyhdisteeseen.Reduction of the keto group with sodium borohydride to the methylene group is a reaction known per se. Applications of the reaction can be found, for example, in the book Fieser &Fieser; Reagents for Organic Synthesis, John Wiley and Sons, vol. 1 (1967), page 1050; butter. 3 (1972), page 263; butter. 4 (1974), page 209. The reaction is generally carried out in aqueous solvents and most often leads to alcohol, but depending on the compounds and conditions it may also lead to the corresponding methylene compound.
Edellä mainitun kirjallisuusviitteen, voi. 3, sivu 263, mukaan reagoi asetofenoni, joka on substituoitu 2- ja 4-asemassa feno-lisilla hydroksyyleillä natriumboorihydridin kanssa kiehuvassa alkaalisessa vesiliuoksessa vastaavaksi etyylibentseenijohdan-naiseksi. Kun kaavan II mukaisen yhdisteen annetaan reagoida vastaavissa olosuhteissa, ei tapahdu toivottua reaktiota.The above literature reference, vol. 3, page 263, reacts with acetophenone substituted in the 2- and 4-positions by phenolic hydroxyls with sodium borohydride in boiling alkaline aqueous solution to give the corresponding ethylbenzene derivative. When the compound of formula II is reacted under similar conditions, the desired reaction does not occur.
Kirjallisuusviitteen G W Gribble, R M Leese (Synthesis 1977, 172-176) mukaan ketoryhmä voidaan pelkistää metyleeniryhmäksi trifluorietikkahapossa, jolloin reaktio menee karbokationin kautta. Pelkistys onnistuu kuitenkin tyydyttävästi vain bentso-f enoni johdanna isilleAccording to the literature reference G W Gribble, R M Leese (Synthesis 1977, 172-176), a keto group can be reduced to a methylene group in trifluoroacetic acid, whereby the reaction goes through a carbocation. However, the reduction is satisfactory only for benzo-phenone derivatives
Saman viitteen mukaan asetofenonijohdannaisilla on saatu päätuotteena dimeroitumistuotetta, joka syntyy, kun karbokationi reagoi aromaattisen renkaan kanssa: + Rr^o\% — f, JiAccording to the same reference, the main product of the acetophenone derivatives is a dimerization product which is formed when the carbocation reacts with an aromatic ring: + Rr ^ o \% - f, Ji
PrPR
Rf^ fH2 R1 -4- 59392Rf ^ fH2 R1 -4- 59392
Lisäksi on tunnettua, että tällaisissa olosuhteissa steerisesti estyneet molekyylit pelkistyvät vain hydroksyylitasolle (G W Gribble et ai., Synthesis 1978, sivut 763-765).Furthermore, it is known that under such conditions, sterically hindered molecules are reduced only to the hydroxyl level (G W Gribble et al., Synthesis 1978, pp. 763-765).
Patenttihakemuksessamme 773 391 käytimme NaBH^-pelkistyksessä happona trifluotietikkahappoa ja havaitsimme, että reaktio menee yllättäen kaavan (II) mukaiselle lähtöaineelle, jolloin tuotteena saadaan metoprololia. Kirjallisuudessa ei vastaavaa reaktiota ole onnistuttu asetofenonijohdannaiselle suorittamaan.In our patent application 773,391, we used trifluoroacetic acid as the acid in the NaBH 4 reduction and found that the reaction surprisingly proceeds to the starting material of formula (II) to give metoprolol as a product. No similar reaction to the acetophenone derivative has been performed in the literature.
Tutkiessamme asiaa edelleen havaitsimme yllättäen, että reaktio menee myös käyttämällä hinnaltaan halpoja metaanisulfonihappoa ja p-tolueenisulfonihappoa. Tämä on sikäli yllättävää, että aikaisemmin ei ole karbokationia (III) saatu muodostumaan käyttämällä sulfonihappojohdannaisia»As we further investigated the matter, we surprisingly found that the reaction also proceeds using inexpensive methanesulfonic acid and p-toluenesulfonic acid. This is surprising in that previously the carbocation (III) has not been formed using sulfonic acid derivatives »
Keksinnön mukaisista reagensseista varsinkin metaanisulfonihappo on paljon edullisempi kuin trifluorietikkahappo. Ensinnäkin se on huomattavasti halvempaa, sen hinta on n. 25 % trifluorietik-kahapon hinnasta. Käytettäessä metaanisulfonihappoa reagenssina päästään myös pienemmillä NaBH^~määrillä, noin kolmasosalla, ja saanto on kuitenkin samaa luokkaa kuin trifluorletikkahapossa. Keksinnön mukainen menetelmä on siten paljon halvempi kuin hakemuksessa n:o 773 391 kuvattu menetelmä. Lisäksi metaanisulfonihappo on hajuton, mikä tekee sen helpommin käsiteltäväksi kuin trifluorietikkahappo, joka on pistävän hajuinen. p-Tolueeni-sulfonihappo on vielä halvempaa kuin metaanisulfonihappo; sen hinta on n. 6 % trifluorietlkkahapon hinnasta.Of the reagents of the invention, methanesulfonic acid in particular is much more preferred than trifluoroacetic acid. Firstly, it is considerably cheaper, costing about 25% of the price of trifluoroacetic acid. When methanesulfonic acid is used as the reagent, smaller amounts of NaBH 4, about one third, are also obtained, and the yield is, however, in the same range as in trifluoroacetic acid. The method according to the invention is thus much cheaper than the method described in application No. 773,391. In addition, methanesulfonic acid is odorless, which makes it easier to handle than trifluoroacetic acid, which has a pungent odor. p-Toluenesulfonic acid is even cheaper than methanesulfonic acid; its price is about 6% of the price of trifluoroacetic acid.
Olemme verranneet keksinnön mukaista menetelmää suomalaisessa hakemuksessa 762 507 kuvattuun menetelmään, ja toteamme, että tässä ei esiinny kaaviossa III esitettyä karbokationivälivaihet-ta. Se on sen takia katsottava reaktiomekanismiltaan toiseksi menetelmäksi.We have compared the process according to the invention with the process described in Finnish application 762 507, and we state that the carbocation cation intermediate shown in Scheme III does not exist here. It must therefore be regarded as a second method with a reaction mechanism.
- 5 - 59392- 5 - 59392
Edelleen olemme tehneet taloudellisuusvertailuja eri menetelmien välillä suorittamalla suomalaisissa hakemuksissa 781 001, 773 391 ja 762 507 kuvatut menetelmät. Saimme seuraavat tulokset merkitsemällä suomalaisen hakemuksen 781 001 menetelmän raaka-ainekustannuksia suhdeluvulla 1: 781 001 (esim. 1) 1.0 781 001 (esim. 2) 1.9 773 391 1.8 762 507 2.0Furthermore, we have made economic comparisons between different methods by performing the methods described in Finnish applications 781,001, 773,391 and 762,507. We obtained the following results by marking the raw material costs of the method of the Finnish application 781 001 with a ratio of 1: 781 001 (eg 1) 1.0 781 001 (eg 2) 1.9 773 391 1.8 762 507 2.0
Taulukosta voimme havaita, että hakemuksessa 781 001 mainitun esimerkin 1 mukaan saadaan ylivoimaisesti halvinta metoprolo-lia. Hinnan halpuus johtuu lähinnä siitä, että reaktiossa käytetään metaanisulfonihappoa, joka on halpa reagenssi* Lisäksi reaktiossa on hyvä saanto. Esimerkissä 2 mainittu menetelmä on kalliimpi, koska saanto on huonompi. Hakemuksessa 781 001 mainittu menetelmä on lisäksi teknisesti erittäin helppo suorittaa, koska siinä on ainoastaan sekoitus lnertissä liuottimessa ja tuotteen eristys. Hakemuksessa 762 507 mainitussa menetelmässä on käytettävä katalyyttistä vedetystä, mikä on teknisesti hankala, vaarallinen ja laitteistoltaan kallis prosessi. Menetelmien erilainen tekninen vaatimustaso ei ilmene taulukosta.It can be seen from the table that according to Example 1 mentioned in application 781 001, by far the cheapest metoprolol is obtained. The cheapness of the price is mainly due to the use of methanesulfonic acid, which is a cheap reagent. * In addition, the reaction has a good yield. The method mentioned in Example 2 is more expensive because the yield is poorer. Furthermore, the process mentioned in application 781 001 is technically very easy to carry out, as it only involves mixing in an inert solvent and isolating the product. The process mentioned in application 762 507 has to use catalytic hydrogenation, which is a technically cumbersome, dangerous and expensive process. The different technical requirements for the methods are not reflected in the table.
Keksinnön mukaisessa hakemuksessa käytetty lähtöaine II valmistetaan hakemuksemme 773 391 mukaisesti. Reaktio natriumboori-hydridin kanssa tapahtuu alhaisessa lämpötilassa noin 0°C:ssa, lnertissä liuottimessa, esimerkiksi metyleenikloridissa, metaanisulfonihapon tai p-tolueenisulfonihapon läsnäollessa.The starting material II used in the application according to the invention is prepared according to our application 773 391. The reaction with sodium borohydride takes place at low temperature at about 0 ° C in an inert solvent such as methylene chloride in the presence of methanesulfonic acid or p-toluenesulfonic acid.
Keksintö kuvataan seuraavissa esimerkeissä: - 6 - 59392The invention is illustrated by the following examples: 6 to 59392
Esimerkki 1 250 ml metyleenikloridia ja 50 ml metaanisulfonihappoa jäähdytetään 0°C:een. Tässä lämpötilassa lisätään vähitellen seos, joka sisältää 10 g l-[4-(metoksimetyylikarbonyyl)fenoksi]-3-iso-propyyliamino-2-propanolia ja 5 g natriumboorihydridiä. Sekoitetaan noin tunnin ajan 0°C:ssa ja annetaan lämpötilan nousta huoneenlämpötilaan. Lisätään vettä ja säädetään pH n. 10:een natriumhydroksidiliuoksella.Example 1 250 ml of methylene chloride and 50 ml of methanesulfonic acid are cooled to 0 ° C. At this temperature, a mixture of 10 g of 1- [4- (methoxymethylcarbonyl) phenoxy] -3-isopropylamino-2-propanol and 5 g of sodium borohydride is gradually added. Stir for about an hour at 0 ° C and allow the temperature to rise to room temperature. Add water and adjust the pH to about 10 with sodium hydroxide solution.
Metyleenikloridifaasi erotetaan, pestään vedellä, kuivataan natriumkarbonaatilla ja haihdutetaan kuiviin. Jäännös kiteytetään esimerkiksi heptaanista. Saadaan 8,1 g (85 %) väritöntä metoprololia, s.p. 45°C. Kun aine tavanmukaisella tavalla muutetaan hydrokloridiksi, saadaan kiteitä, joiden sulamispiste on 83°C, ja vastaavan tartraatin s.p. on 118-120°C.The methylene chloride phase is separated, washed with water, dried over sodium carbonate and evaporated to dryness. The residue is crystallized, for example, from heptane. 8.1 g (85%) of colorless metoprolol are obtained, m.p. 45 ° C. When the substance is converted to the hydrochloride in a conventional manner, crystals with a melting point of 83 ° C are obtained, and the corresponding tartrate m.p. is 118-120 ° C.
Esimerkki 2 150 g kuivaa p-tolueenisulfonihappoa ja 400 ml metyleenikloridia jäähdytetään 0°C:een. Lisätään seos, joka sisältää 10 g 1— [4— (metoksimetyylikarbonyyli)fenoksi]-3-isopropyyliamino-2-propano-lia ja 20 g natriumboorihydridiä 0°C:ssa ja jatketaan niin kuin esimerkissä 1. Saadaan 5,0 g (52,6 %) metoprololia, s.p. 45°C.Example 2 150 g of dry p-toluenesulfonic acid and 400 ml of methylene chloride are cooled to 0 ° C. Add a mixture of 10 g of 1- [4- (methoxymethylcarbonyl) phenoxy] -3-isopropylamino-2-propanol and 20 g of sodium borohydride at 0 ° C and proceed as in Example 1. 5.0 g (52 g) of , 6%) metoprolol, m.p. 45 ° C.
Claims (1)
Priority Applications (8)
| 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 |
| NO790825A NO145402C (en) | 1978-04-01 | 1979-03-12 | PROCEDURE FOR THE PREPARATION OF A THERAPEUTIC ACTIVE PROPANOLAMINE, METOPROLOL |
| AT0196479A AT364349B (en) | 1978-04-01 | 1979-03-15 | METHOD FOR PRODUCING 1-ISOPROPYLAMINO-3- (P- (2-METHOXYAETHYL) PHENOXY) -PROPAN-2OL AND ITS ACID ADDITION SALTS |
| NL7902407A NL7902407A (en) | 1978-04-01 | 1979-03-28 | PROCESS FOR THE PREPARATION OF A THERAPEUTICALLY ACTIVE PROPANOLAMINE; PHARMACEUTICAL PREPARATION CONTAINING THE PROPANOLAMINE SO PREPARED. |
| SE7902821A SE444677B (en) | 1978-04-01 | 1979-03-29 | PROCEDURE FOR PREPARING 1-ISOPROPYLAMINO-3- / 4- (2-METOXYETHYL) PHENOXY / -2-PROPANOL |
| CH301279A CH639065A5 (en) | 1978-04-01 | 1979-03-30 | Process for the preparation of 1-isopropylamino-3-[4-(2-methoxy- ethyl)phenoxy]-2-propanol |
| JP3923679A JPS54145623A (en) | 1978-04-01 | 1979-03-30 | Manufacture of 11isopropylaminoo33*44*22 methoxyethyl*phenoxy**22propanol or its salt |
| DK131079A DK145195C (en) | 1978-04-01 | 1979-03-30 | METHOD FOR PREPARING 1-ISOPROPYLAMINO-3- (4- (2-METOXYAETHYL) -PHENOXY) -2-PROPANOL OR ACID ADDITION SALTS THEREOF |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FI781001 | 1978-04-01 | ||
| 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 |
|---|---|
| FI781001A FI781001A (en) | 1979-10-02 |
| FI59392B FI59392B (en) | 1981-04-30 |
| FI59392C true FI59392C (en) | 1982-02-02 |
Family
ID=8511594
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| 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 |
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 JP JP3923679A patent/JPS54145623A/en active Granted
- 1979-03-30 DK DK131079A patent/DK145195C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO790825L (en) | 1979-10-02 |
| AT364349B (en) | 1981-10-12 |
| CH639065A5 (en) | 1983-10-31 |
| ATA196479A (en) | 1981-03-15 |
| NO145402C (en) | 1982-03-17 |
| NL7902407A (en) | 1979-10-03 |
| JPS6130653B2 (en) | 1986-07-15 |
| SE444677B (en) | 1986-04-28 |
| DK131079A (en) | 1979-10-02 |
| DK145195C (en) | 1983-04-05 |
| JPS54145623A (en) | 1979-11-14 |
| FI781001A (en) | 1979-10-02 |
| NO145402B (en) | 1981-12-07 |
| DK145195B (en) | 1982-10-04 |
| SE7902821L (en) | 1979-10-02 |
| FI59392B (en) | 1981-04-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Magasanik et al. | The separation and identification of ketoacids by filter paper chromatography | |
| Malebari et al. | β-Lactam analogues of combretastatin A-4 prevent metabolic inactivation by glucuronidation in chemoresistant HT-29 colon cancer cells | |
| US20210363121A1 (en) | Notch inhibitors for use in the treatment of t-cell acute lymphoblastic leukemia | |
| EP3571183B1 (en) | 3-(phenyl)-2-(aminomethyl)-1-phenyl-2-propen-1-one derivatives as inhibitors of the n-terminal domain of the androgen receptor for treating prostate cancer | |
| FI59392C (en) | PROFESSIONAL PROTECTION FOR THERAPEUTIC ACTIVATION 1-ISOPROPYLAMINO-3- (4- (2-METHOXYTHYL) PHENOXY) -2-PROPANOL SAMT DESS SYRAADDITIONSSALTER | |
| SU1329615A3 (en) | Method of producing derivatives of alkanes or alkenes | |
| Schneider | 2-Alkyl-substituted 1, 1-bis (4-acetoxyphenyl)-2-phenylethenes. Estrogen receptor affinity, estrogenic and antiestrogenic properties, and mammary tumor inhibiting activity | |
| Djerassi et al. | Alkaloid Studies. XVII. 1 The Structure of the Cactus Alkaloid Pilocereine2 | |
| FR2625998A1 (en) | PROCESS FOR PREPARING HYDROXYALKYL-1-METHYL-2-NITRO-5-IMIDAZOLES | |
| EP0364350B1 (en) | 4-Methyl-5[2-(4-phenyl-1-piperazinyl)-ethyl] thiazole derivatives, their preparation and pharmaceutical compositions containing them | |
| US3987105A (en) | Process for methoxymethylation of phenolic hydroxyl groups | |
| Narwanti et al. | Conventional and Microwave-Assisted Synthesis of 4’-Bromochalchone Utilizing 4-Bromoacetophenone and Benzaldehyde as Starting Material in Alkaline Condition | |
| FR2463121A1 (en) | DERIVATIVES OF 1,1,2-TRIPHENYLPROPANE AND 1,1,2-TRIPHENYLPROPENE, PROCESS FOR PREPARING THESE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THESE COMPOUNDS | |
| KAMAL et al. | The Chemistry of Pyrazine and Its Derivatives. VII. The Synthesis of Vinylpyrazine and Substituted Vinylpyrazines1 | |
| FI85465B (en) | FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA 4-FENYLPROPYL-INDOLDERIVAT. | |
| EP0017523B1 (en) | Dithiepinno (1,4)(2,3-c) pyrrol derivatives, their preparation and pharmaceutical compositions containing them | |
| Cavalleri et al. | Synthesis and biological activity of two metabolites of 1-methyl-5-(1-methylethyl)-2-nitro-1H-imidazole, an antiprotozoal agent | |
| FI58491B (en) | PROCEDURE FOR THE FRAMSTATION OF AV 1-ISOPROPYLAMINO-3- (4- (2-METHOXYTHYL) PHENOXY) -2-PROPANOL WITH THERAPEUTIC ACTIVITY SAMT SYRA ADDITIONAL SALT DAERAV | |
| EP0347305B1 (en) | [(Aryl-4-piperazinyl-1)-2-ethoxy]-3 p cymene, the ortho-, meta-, para-monosubstituted or disubstituted phenyl ring derivatives, process for their preparation and medicaments containing the same as the active principle | |
| Dullaghan et al. | 5-Nitro-2-thenaldehyde | |
| FI61869C (en) | PROFESSIONAL FORM OF THERAPEUTIC ACTIVATION 1-ISOPROPYLAMINO-3- (4- (2-METHOXYTHYL) PHENOXY) -2-PROPANOL SAMT DESS SYRA ADDITIONAL SALT | |
| Tănase et al. | A long-range tautomeric effect on a new Schiff isoniazid analogue, evidenced by NMR study and X-ray crystallography | |
| Haddlesey et al. | 1009. 1-Aminoindoles: a novel rearrangement of 1, 4-dihydrocinnolines | |
| Meador | Exploration of Carbon-Oxygen and Carbon-Nitrogen Bond Formation Utilizing Trichloroacetimidates and Investigations of New Reactions Mediated by Oxoammonium Salts | |
| Rogic et al. | Nitrosation in organic chemistry. 1-Hydroxy-2-(. omega.-methoxycarbonylbutyl)-4, 5, 6, 7-tetrahydrobenzimidazole 3-oxide. An unusual product from the nitrosation of cyclohexanone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM | Patent lapsed |
Owner name: FARMOS-YHTYMAE OY |