DK156567B - Fremgangsmaade til fremstilling af metoprolol - Google Patents

Fremgangsmaade til fremstilling af metoprolol Download PDF

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Publication number
DK156567B
DK156567B DK542082A DK542082A DK156567B DK 156567 B DK156567 B DK 156567B DK 542082 A DK542082 A DK 542082A DK 542082 A DK542082 A DK 542082A DK 156567 B DK156567 B DK 156567B
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DK
Denmark
Prior art keywords
phenoxy
methoxyethyl
formula
metoprolol
isopropylamine
Prior art date
Application number
DK542082A
Other languages
English (en)
Other versions
DK542082A (da
DK156567C (da
Inventor
Erkki Juhani Honkanen
Pekka Juhani Kairisalo
Pentti Tapio Nore
Veijo Olavi Ikonen
Aino Kyllikki Pippuri
Original Assignee
Haessle Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Haessle Ab filed Critical Haessle Ab
Publication of DK542082A publication Critical patent/DK542082A/da
Publication of DK156567B publication Critical patent/DK156567B/da
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Publication of DK156567C publication Critical patent/DK156567C/da

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/33—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Saccharide Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Description

DK 156567B
Den foreliggende opfindelse angâr en særlig fremgangs-mâde til fremstilling af metoprolol eller 1-isopropylamino- 3-(4-(2-metoxyætyl)-fenoxy)-2-propanol med formlen 5 /CH3
CH-.0CH-CHo*\ >0CHoCHCHoNHCH I
3 2 2 \=/ 21 2 \ OH CH3 10 Metoprolol er et kendt terapeutisk middel.
SE patentskrift nr. 354.851 beskriver forskellige frem-gangsmâder til fremstilling af metoprolol. Den bedste af disse fremgangsmâder er sandsynligvis den hvori en forbindelse med formlen 15
CH3OCH2CH2 {3-och2ch —^H2 II
2q omsættes med isopropylamin. Udbytte ved denne fremgangsmâde er imidlertid kun ca. 50%. Dette skyldes hovedsageligt de uonske-de bireaktioner der fx forer til den tilsvarende isomere l-pro-panol. Bireaktioner forstyrrer ogsâ fremstillingen af forbindel-sen med formel II.
23 Den publicerede japanske patentansogning nr. 57-2246 (refereret i Chem. Abstr. 97:5962) beskriver fx en fremgangsmâde til fremstilling af l-isopropylamino-3-(2-allyl)-fenoxy-2-propanol, hvor en forbindelse med formlen 30 /CH2CH=CH2 <^-och2ch— ch2 m
OH OH
omsættes med tionylklorid i diætylæter i nærværelse af pyridin til dannelse af 4-((2-allylfenoxy)-metyl)-1,3,2-dioxatiolan som derpâ autoklaveres med isopropylamin i dimetylformamid i 2 dage.
35 2
DK 156567 B
Det har nu vist sit at metoprolol kan fremstilles nâr 3- (4-(2-metoxyætyl)-fenoxy)-l,2-propandiol med formlen c CHo0CH~CHo—y /—OCH~CH CH0
5 3 2 2 2| | 2 IV
OH OH
omsættes med tionylklorid i diklormetan i nærværelse af en ækvivalent mængde trialkylamin til dannelse af 4-(4-((2-metoxy- 10 æty1)-fenoxy)-metyl)-1,3,2-dioxatiolan-2-oxyd med formlen CHo0CHoCHo—x %-OCH-Ca CH0
15 5 Z Z / z | | Z
0 0 V
\/ 0 2q som derpâ omsættes med isopropylamin i acetonitril.
Fremgangsmâden gennemf0res fortrinsvis som beskrevet i det efterf0lgende eksempel.
Forbindelsen med formel IV kan fremstilles ud fra 4- (2-metoxyætyl)-fenol og glycidol i nærværelse af en base-25 katalysator.
Med fremgangsmâden ifolge opfindelsen kan metoprolol fremstilles i et godt udbytte (ca. 77%s omdannelse af forbindelsen med formel IV). Det vundne produkt er meget rent, dvs. der dannes kun en usignifikant mængde af den isomere 3Q 1-propanol.
Fremgangsmâden if0lge den japanske ansogning nr. 57-2246 kan îkke iiensigtsmæssigt anvendes til industriel fremstilling pâ grand af at der anvendes diætylæter i det f0rste trin og at der kræves lang reaktionstid i fremgangsmâdens andet trin.
35 Derimod kan reaktionerne ved fremgangsmâden ifolge opfindelsen gennemf^res let og pâ 0konomisk mâde ogsâ i industriel mâle-stok.
Fremgangsmâden ifolge opfindelsen belyses nærmere i 3 DK 1565671 det f0lgende ved hjælp af et eksempel.
Eksempel a) 4-(4-(2-Metoxyætyl)-fenoxy)-metyl-l,3,2-dioxatiolan- 2-oxyd (V)________ 22,6 g (0,1 mol) 3-(4-(2-metoxyætyl)-fenoxy)-1,2-propan-diol og 10,1 g (0,1 mol) triætylamin opleses i 100 ml diklor-metan. 7,3 ml tionylklorid i 10 ml diklormetan sættes til op-l0sningen ved 0°C. Blandingen omr0res i 15 minutter ved 0-5°C, vaskes med 0,1N saltsyre og vand og t0rres med Na2SO^. Oples-ningen inddampes til t0rhed under vakuum·. Der vindes 25,8 g (95%) af det 0nskede produkt; 1H-NMR: 2,76 (2Ht), 3,27(3Hs), 3,50(2Ht), 3,76-4,81(4Hm), 5,20(1 H kvartet), 6,66(2Hd), 7,03(2Hd).
15 b) _l-lsopropylamino-3-(4-(2-metoxyætyl)-fenoxy)-2-propanol 2,74 g (0,01 aol) af forbindelse V og 7 ml isopropyl- amin koges under tilbagesvaling i 25 ml acetonitril i 20 ti-
mer. Opl0sningsmidlerne fjernes, der sættes 25 ml IN NaOH
til remanensen og blandingen ekstraheres med ætylacetat. Eks- trakten vaskes med vand og terres. Derpâ tilsættes en ækvivalent mængde vinsyre i metanol for at tilvejebringe 2,79 g (81%) af det Onskede produkt i form af tartratet deraf med smp.
114-116°C.
25 30 35

Claims (4)

1. Fremgangsmâde til fremstilling af 1-isopropylamino- 3-(4-(2-metoxyætyl)-fenoxy)-2-propanol med formlen
5 J~\ Z™3 CH-OCH^CH^-C' ')-OCH-CHCH„NHCH 3 2 2 \SSJ 2| 2 \ OH CH3 kendetegnet ved at 3-(4-(2-metoxyætyl)-fenoxy)-10 1,2-propandiol med formlen OH 15 omsættes med tionylklorid i diklormetan i nærværelse af en ækvivalent mængde trialkylamin til dannelse af 4-(4-((2-me-toxyætyl)-fenoxy)-metyl)-1,3,2-dioxatiolan-2-oxyd med formlen 20 CHoOCH0CH0—v \-OCH0CH - CH0 3 2 2 \=/ 21 I 2 o o V 25 0 som derpâ omsættes med isopropylamin i acetonitril.
2. Fremgangsmâde ifolge krav 1, kendetegnet ved at omsætningen mellem 3-(4-(2-metoxyætyl)-fenoxy)-1,2-propan-diol og tionylklorid gennemfores ved 0-5°C i ca. 15 minutter.
3. Fremgangsmâde ifolge krav 1 eller 2, kendetegnet ved at omsætningen mellem 4-(4-((2-metoxyætyl)-fenoxy)-metyl)-1,3,2-dioxatiolan-2-oxyd og isopropylamin gennemfores ved ca. 80°C i ca. 20 timer.
^ 4. Fremgangsmâde ifolge et hvilket som helst af de fore- gâende krav, kendetegnet ved at trialkylaminen er triætylamin.
DK542082A 1981-12-17 1982-12-07 Fremgangsmaade til fremstilling af metoprolol DK156567C (da)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI814053 1981-12-17
FI814053 1981-12-17

Publications (3)

Publication Number Publication Date
DK542082A DK542082A (da) 1983-06-18
DK156567B true DK156567B (da) 1989-09-11
DK156567C DK156567C (da) 1990-03-05

Family

ID=8514961

Family Applications (2)

Application Number Title Priority Date Filing Date
DK542082A DK156567C (da) 1981-12-17 1982-12-07 Fremgangsmaade til fremstilling af metoprolol
DK541982A DK541982A (da) 1981-12-17 1982-12-07 Fremgangsmaade til fremstilling af acebutolol

Family Applications After (1)

Application Number Title Priority Date Filing Date
DK541982A DK541982A (da) 1981-12-17 1982-12-07 Fremgangsmaade til fremstilling af acebutolol

Country Status (9)

Country Link
JP (2) JPS58159449A (da)
KR (1) KR840002768A (da)
CA (1) CA1198125A (da)
DK (2) DK156567C (da)
HU (1) HU186649B (da)
NO (2) NO155619C (da)
SE (2) SE452612B (da)
SU (1) SU1170968A3 (da)
YU (2) YU275882A (da)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56152461A (en) * 1980-04-30 1981-11-26 Ota Seiyaku Kk Preparation of indole derivative

Also Published As

Publication number Publication date
JPS58159449A (ja) 1983-09-21
SE8207199D0 (sv) 1982-12-16
NO155619C (no) 1987-04-29
SE452612B (sv) 1987-12-07
SE8207198L (sv) 1983-06-18
NO824233L (no) 1983-06-20
KR840002768A (ko) 1984-07-16
SE8207198D0 (sv) 1982-12-16
SE8207199L (sv) 1983-06-18
DK541982A (da) 1983-06-18
YU275882A (en) 1985-03-20
JPS58159446A (ja) 1983-09-21
HU186649B (en) 1985-08-28
DK542082A (da) 1983-06-18
DK156567C (da) 1990-03-05
SU1170968A3 (ru) 1985-07-30
YU275982A (en) 1985-03-20
NO824232L (no) 1983-06-20
NO155619B (no) 1987-01-19
CA1198125A (en) 1985-12-17

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