DE2905053A1 - 1-Methyl:indolyl:oxy-2,3-epoxy-propane prodn. - from 4-hydroxy-2-methyl:indole and epichlorohydrin in protic solvent - Google Patents

1-Methyl:indolyl:oxy-2,3-epoxy-propane prodn. - from 4-hydroxy-2-methyl:indole and epichlorohydrin in protic solvent

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Publication number
DE2905053A1
DE2905053A1 DE19792905053 DE2905053A DE2905053A1 DE 2905053 A1 DE2905053 A1 DE 2905053A1 DE 19792905053 DE19792905053 DE 19792905053 DE 2905053 A DE2905053 A DE 2905053A DE 2905053 A1 DE2905053 A1 DE 2905053A1
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DE
Germany
Prior art keywords
methyl
hydroxy
epichlorohydrin
prodn
protic solvent
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
DE19792905053
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German (de)
Other versions
DE2905053C2 (en
Inventor
Josef Dr Hader
Klaus Dr Junghans
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
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 Schering AG filed Critical Schering AG
Priority to DE19792905053 priority Critical patent/DE2905053A1/en
Publication of DE2905053A1 publication Critical patent/DE2905053A1/en
Application granted granted Critical
Publication of DE2905053C2 publication Critical patent/DE2905053C2/de
Granted legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Prodn. of 1-(2-methylindol-4-yloxy)-2,3-epoxypropane (I) comprises reacting 4-hydroxy-2-methylindole (II) and epichlorohydrin (III) in a protic solvent in presence of an alkali metal salt of a weak acid or of Al2O3, at above room temp. (I) is an intermediate for mepindolol (4-(2-hydroxy-3-isopropylaminopropxy)-2-methylindole). This process is quicker and gives better yields than the known reaction of (II) and (III) at room temp. in presence of aq. NaOH.

Description

Verfahren zur Herstellung von l-(2-Nethylindol-Process for the preparation of l- (2-Nethylindole-

4-yloxy)-2.3-epoxypropan Die Erfindung betrifft ein Verfahren zur Herstellung von l-(2-Methylindol-4-yloxy)-2.3-epoxypropan aus 4-Hydroxy- 2-methylindol und Epichlorhydrin.4-yloxy) -2.3-epoxypropane The invention relates to a Process for the preparation of l- (2-methylindol-4-yloxy) -2.3-epoxypropane from 4-hydroxy 2-methylindole and epichlorohydrin.

Aus der DT AS 1 620 342 ist bekannt, daß bei der Umsetzung von 4-Hydroxy-2-methylindol mit Epichlorhydrin in Gegenwart von wässrigem Natriumhydroxid bei Raumtemperatur 1- (2-Methylindol-4-yloxy)-2. 3-epoxypropan als Zwischenprodulct entsteht.From DT AS 1 620 342 it is known that in the implementation of 4-hydroxy-2-methylindole with epichlorohydrin in the presence of aqueous sodium hydroxide at room temperature 1- (2-methylindol-4-yloxy) -2. 3-epoxypropane is created as an intermediate product.

Dieses Verfahren hat jedoch den Nachteil, daß die Reaktion relativ langsam verläuft und nur zu unbefriedigenden Ausbeuten in der Größenordnung von 50 ,ó d. Th. führt.However, this method has the disadvantage that the reaction is relatively proceeds slowly and only leads to unsatisfactory yields of the order of magnitude 50, ó d. Th. Leads.

Die erfindungsgemäße Aufgabe lag darin, ein Verfahren bereitzustellen, das in einfacher Weise und kürzerer Zeit bessere Ausbeuten liefert.The object of the invention was to provide a method which gives better yields in a simple manner and in a shorter time.

Die erfindungsgemäße Aufgabe wurde dadurch gelöst, daß man die Reaktion in einem protischen Lösungsmittel in Gegenwart eines Alkalimetallsalzes einer schwachen Säure oder in Gegenwart von Aluminiumoxid bei Temperaturen oberhalb Raumtemperatur durchführt.The object of the invention has been achieved by starting the reaction in a protic solvent in the presence of an alkali metal salt of a weak Acid or in the presence of aluminum oxide at temperatures above room temperature performs.

Unter protischen Lösungsmitteln sind beispielsweise niedere aliphatische Alkohole wie Methanol oder Äthanol zu verstehen. Aber auch Wasser ist geeignet.Protic solvents include, for example, lower aliphatic solvents To understand alcohols such as methanol or ethanol. But water is also suitable.

Unter Alkalisalzen schwacher Säuren sind beispielsweise die Carbonate, Phosphate, Sulfide und Sulfite von Natrium und Kalium zu verstehen. Das Aluminiumoxid wird in handelsüblicher Beschaffenheit verwendet.Among the alkali salts of weak acids are, for example, the carbonates, To understand phosphates, sulphides and sulphites of sodium and potassium. The aluminum oxide is used in a commercial quality.

Die Reaktion läßt sich zwar auch schon bei Raumtemperatur durchführen, jedoch ist der Reaktionsverlauf oberhalb Raumtemperatur so, daß die Reaktion nach kurzer Zeit praktisch quantitativ abgelaufen ist. Ein zweckmäßiger Temperaturbereich ist 50 bis lOb OC.The reaction can be carried out even at room temperature, however, the course of the reaction above room temperature is such that the reaction after has expired practically quantitatively in a short time. A reasonable temperature range is 50 to 10 OC.

Das erfindungsgemäß hergestellte Endprodukt ist ein Zwischenprodukt zur Herstellung von Mepindolol (=4-(2-Hydroxy-3-isopropylamino-propoxy)-2-methylindol).The end product produced according to the invention is an intermediate product for the production of Mepindolol (= 4- (2-Hydroxy-3-isopropylamino-propoxy) -2-methylindole).

Die nachfolgenden Beispiele sollen das erfindungsgemäße Verfahren erläutern.The following examples are intended to illustrate the process according to the invention explain.

Beispiel 1 10 g 4-Hydroxy-2-methylindol in 100 ml Methanol werden mit 30 ml Epichlorhydrin und 10 g Kaliumcarbonat 1 Stunde unter Rückfluß erhitzt. Nach Filtration wird im Vakuum eingedampft und aus i-Propanol kristallisiert. Man erhält 12,4 g (90 % d.Th.) l-(2-Methylindol-4-yloxy)-2.3-epoxypropan vom Schmelzpunkt 97-99 °C, W 265: 10100.Example 1 10 g of 4-hydroxy-2-methylindole in 100 ml of methanol become heated under reflux for 1 hour with 30 ml of epichlorohydrin and 10 g of potassium carbonate. After filtration, it is evaporated in vacuo and crystallized from i-propanol. Man receives 12.4 g (90% of theory) of 1- (2-methylindol-4-yloxy) -2.3-epoxypropane with a melting point 97-99 ° C, W 265: 10100.

Beispiel 2 10 g 4-IIydroxy-2-methylindol in 100 ml i-Propanol werden mit 50 ml Epichlorhydrin und 20 g Aluminiumoxid (bas., Akt.I) 2 Stunden unter Rückfluß erhitzt. Nach Filtration wird im Vakuum zur Trockne eingeengt und der Rückstand aus i-Propanol kristallisiert. Man erhält 13,1 g (95 % d.Th.) 1-(2-Methylindol-4-yloxy)-2.3-epoxypropan vom Schmelzpunkt 98-100 OC (UV265: 10000).Example 2 10 g of 4-II-hydroxy-2-methylindole in 100 ml of i-propanol become with 50 ml epichlorohydrin and 20 g aluminum oxide (bas., Akt.I) for 2 hours under reflux heated. After filtration, it is concentrated to dryness in vacuo and the residue crystallized from i-propanol. 13.1 g (95% of theory) of 1- (2-methylindol-4-yloxy) -2.3-epoxypropane are obtained with a melting point of 98-100 OC (UV265: 10000).

Beispiel 3 10 g 4-Hydroxy-2-methylindol in 100 ml Äthanol werden mit 50 ml Epichlorhydrin und 10 g Natriumphosphat 3 Stunden unter Rückfluß erhitzt. Nach Filtration wird im Vakuum zur Trockne eingeengt und der Rückstand aus i-Propanol kristallisiert. Man erhält 12,7 S (92 % d,Th.) 1-(2-Methylindol-4-yloxy)-2.3-epoxypropan vom Schmelzpunkt 96-98 OC W265: '9950) .Example 3 10 g of 4-hydroxy-2-methylindole in 100 ml of ethanol are mixed with 50 ml of epichlorohydrin and 10 g of sodium phosphate are heated under reflux for 3 hours. After filtration, it is concentrated to dryness in vacuo and the residue is obtained from i-propanol crystallized. 12.7 S (92% of theory) 1- (2-methylindol-4-yloxy) -2.3-epoxypropane are obtained of melting point 96-98 OC W265: '9950).

Claims (1)

Patent a n s p r u c h Verfahren zur Herstellung von l-(2-Methylindol-4-yloxy)-2.3-epoxypropan aus 4-Hydroxy-2-methylindol und Epichlorhydrin, dadurch gekennzeichnet, daß man die Reaktion in einem protischen Lösungsmittel in Gegenwart eines Alkalimetall salzes einer schwachen Säure oder Aluminiumoxid oberhalb Raumtemperatur durchführt. Patent a n s p r u c h Process for the production of l- (2-methylindol-4-yloxy) -2.3-epoxypropane from 4-hydroxy-2-methylindole and epichlorohydrin, characterized in that one the reaction in a protic solvent in the presence of an alkali metal salt a weak acid or alumina above room temperature.
DE19792905053 1979-02-08 1979-02-08 1-Methyl:indolyl:oxy-2,3-epoxy-propane prodn. - from 4-hydroxy-2-methyl:indole and epichlorohydrin in protic solvent Granted DE2905053A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DE19792905053 DE2905053A1 (en) 1979-02-08 1979-02-08 1-Methyl:indolyl:oxy-2,3-epoxy-propane prodn. - from 4-hydroxy-2-methyl:indole and epichlorohydrin in protic solvent

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DE19792905053 DE2905053A1 (en) 1979-02-08 1979-02-08 1-Methyl:indolyl:oxy-2,3-epoxy-propane prodn. - from 4-hydroxy-2-methyl:indole and epichlorohydrin in protic solvent

Publications (2)

Publication Number Publication Date
DE2905053A1 true DE2905053A1 (en) 1980-08-14
DE2905053C2 DE2905053C2 (en) 1989-08-10

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Application Number Title Priority Date Filing Date
DE19792905053 Granted DE2905053A1 (en) 1979-02-08 1979-02-08 1-Methyl:indolyl:oxy-2,3-epoxy-propane prodn. - from 4-hydroxy-2-methyl:indole and epichlorohydrin in protic solvent

Country Status (1)

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DE (1) DE2905053A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1905881A1 (en) * 1968-02-09 1969-09-25 Sandoz Ag Process for the preparation of new heterocyclic compounds
DE1620342B2 (en) * 1965-02-01 1973-10-04 Sandoz Ag, Basel (Schweiz)
DE2508251A1 (en) * 1975-02-26 1976-09-09 Boehringer Mannheim Gmbh 4-(3-Amino 2-hydroxypropoxy) indoles - with beta-blocking activity for treating cardiovascular disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1620342B2 (en) * 1965-02-01 1973-10-04 Sandoz Ag, Basel (Schweiz)
DE1905881A1 (en) * 1968-02-09 1969-09-25 Sandoz Ag Process for the preparation of new heterocyclic compounds
DE2508251A1 (en) * 1975-02-26 1976-09-09 Boehringer Mannheim Gmbh 4-(3-Amino 2-hydroxypropoxy) indoles - with beta-blocking activity for treating cardiovascular disorders

Also Published As

Publication number Publication date
DE2905053C2 (en) 1989-08-10

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D2 Grant after examination
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8327 Change in the person/name/address of the patent owner

Owner name: SCHERING AG, 13353 BERLIN, DE

8339 Ceased/non-payment of the annual fee