DE1135464B - Process for the preparation of dextrorotatory, multiply substituted tetrahydro-1,4-oxazines - Google Patents

Process for the preparation of dextrorotatory, multiply substituted tetrahydro-1,4-oxazines

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Publication number
DE1135464B
DE1135464B DER17625A DER0017625A DE1135464B DE 1135464 B DE1135464 B DE 1135464B DE R17625 A DER17625 A DE R17625A DE R0017625 A DER0017625 A DE R0017625A DE 1135464 B DE1135464 B DE 1135464B
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Germany
Prior art keywords
phenyl
dextrorotatory
oxazines
morpholine
methyl
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Pending
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DER17625A
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German (de)
Inventor
Dr Harm Siemer
Dr Adolf Doppstadt
Dipl-Chem Margarete Pickel
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Ravensberg GmbH Chemische Fabrik
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Ravensberg GmbH Chemische Fabrik
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Priority to DER17625A priority Critical patent/DE1135464B/en
Publication of DE1135464B publication Critical patent/DE1135464B/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/54—Three nitrogen atoms

Description

Verfahren zur Herstellung von rechtsdrehenden, mehrfach substituierten Tetrahydro-1,4-oxazinen Von den substituierten Tetrahydro-1,4-oxazinen (Morpholin) hat das 2-Phenyl-3-methyl-tetrahydro-1,4-oxazin Bedeutung als hungerdämpfendes und psychostimulierendes Mittel erlangt. Es ist als Racemat in Form seines Hydrochlorids oder 8-Chlortheophyllinats bekannt. Die Gewinnung der optisch aktiven Verbindung unter Anwendung der üblichen chemischen bzw. physikalischen Methoden in technischem Ausmaß ist bisher nicht gelungen, weshalb die therapeutische Verwendung dieses Morpholinderivates in optisch aktiver Form, z. B, als rechtsdrehende Verbindung, bisher nicht möglich gewesen ist.Process for the production of clockwise, multiply substituted Tetrahydro-1,4-oxazines Of the substituted tetrahydro-1,4-oxazines (morpholine) 2-phenyl-3-methyl-tetrahydro-1,4-oxazine has importance as an anti-hunger and psychostimulating agent obtained. It is available as a racemate in the form of its hydrochloride or 8-chlorotheophyllinate known. Obtaining the optically active compound using the usual chemical or physical methods in technical Extent has so far not been successful, which is why the therapeutic use of this morpholine derivative in optically active form, e.g. B, as a clockwise connection, not yet possible has been.

Die Erfindung betrifft nun ein Verfahren zur Herstellung der noch nicht bekannten, rechtsdrehenden Tetrahydro-1,4-oxazine der allgemeinen Formel (I) worin R,. einen niederen Alkylrest und R2 ein Wasserstoffatom oder einen niederen Alkylrest bedeutet, oder deren Salzen, das dadurch gekennzeichnet ist, daß man linksdrehende Diäthanolamine der Formel (II) worin R1 und R2 die oben erläuterte Bedeutung zukommt, in an sich bekannter Weise mit wasserabspaltenden Mitteln, z. B. konzentrierter Schwefelsäure behandelt und gegebenenfalls anschließend nach üblichen Methoden in ihre Salze überführt.The invention now relates to a process for the preparation of the as yet unknown, dextrorotatory tetrahydro-1,4-oxazines of the general formula (I) wherein R ,. a lower alkyl radical and R2 is a hydrogen atom or a lower alkyl radical, or salts thereof, which is characterized in that levorotatory diethanolamines of the formula (II) where R1 and R2 have the meaning explained above, in a manner known per se with dehydrating agents, eg. B. treated concentrated sulfuric acid and optionally then converted into their salts by customary methods.

Die erforderlichen Ausgangssubstanzen der Formel (1I) kann man sehr günstig in technischem Maßstabe gewinnen, indem man beispielsweise linksdrehendes Phenylacetylcarbinol, welches nach einem Gärungsverfahren zugänglich ist (Biochem. Z., 115 [1921], S. 282; 127 [1922], S. 327), unter Erhaltung der optischen Aktivität in Gegenwart von Aminoäthanol aminierend hydriert oder auch L-1-Phenyl-2-aminopropanol-(1) bzw. L-1-Phenyl-2-methylamino-propanol-(1) mit 1 Mol Äthylenoxyd zur Reaktion bringt.The required starting substances of the formula (1I) can be obtained very cheaply on an industrial scale by adding, for example, levorotatory phenylacetylcarbinol, which is accessible after a fermentation process (Biochem. Z., 115 [1921], p. 282; 127 [1922], p . 327), while maintaining the optical activity in the presence of aminoethanol aminating hydrogenated or L-1-phenyl-2-aminopropanol- (1) or L-1-phenyl-2-methylamino-propanol- (1) with 1 mol Ethylene oxide reacts.

Die Ringschlußreaktion kann man sowohl mit den Basen nach Formel (II) als auch mit deren Salzen durchführen, z. B. durch Umsetzung mit konzentrierter Schwefelsäure (spez. Gewicht 1,84) unter äußerer Kühlung oder gegebenenfalls auch ohne Kühlung. Hierbei ist es ein Vorteil, die Reaktionslösung zur Abkürzung der Reaktionszeit und zur vollkommenen Umsetzung auf höhere Temperaturen, beispielsweise 90'C zu erwärmen.The ring closure reaction can be carried out either with the bases according to formula (II) or with their salts, e.g. B. by reaction with concentrated sulfuric acid (specific weight 1.84) with external cooling or optionally without cooling. It is an advantage here to heat the reaction solution to higher temperatures, for example 90.degree. C., in order to shorten the reaction time and for complete conversion.

Bemerkenswerterweise drehen die Ringschlußverbindungen die Ebene des polarisierten Lichtes umgekehrt wie ihre Ausgangsprodukte. Zum Beispiel weist L-1-Phenyl-2-(ß-hydroxyäthylamino)-propanol-(1) eine Drehung [a] e = -6' (in Methanol) auf, während das hieraus entstandene D-2-Phenyl-3-methyl-morpholin bei [a] e = -I-22,2° (in Methanol) dreht.It is noteworthy that the ring closure compounds rotate the plane of polarized light in the opposite direction to that of their parent products. For example, L-1-phenyl-2- (ß-hydroxyethylamino) propanol- (1) has a rotation [a] e = -6 ' (in methanol), while the resulting D-2-phenyl-3- methyl-morpholine rotates at [a] e = -I-22.2 ° (in methanol).

Aus den nach dem erfindungsgemäßen Verfahren erhaltenen, rechtsdrehenden Morpholinen lassen sich in bekannter Weise deren ebenfalls rechtsdrehende Salze herstellen, z. B. deren Hydrochloride oder Theophyllinate bzw. Halogentheophyllinate.From the clockwise obtained by the process according to the invention Morpholines can also be dextrorotatory salts thereof in a known manner manufacture, e.g. B. their hydrochlorides or theophyllinates or halo theophyllinates.

Die erfindungsgemäß herstellbaren, rechtsdrehenden Tetrahydro-1,4-oxazine sind wertvolle Arzneimittel, welche sich beispielsweise vom nächst ähnlichen, racemischen 2-Phenyl-3-methyl-morpholin-H Cl in vorteilhafter Weise unterscheiden. Der hierdurch erzielte Fortschritt soll durch nachstehende Vergleiche erläutert werden 1. Akute Toxizität (subkutane Injektion an männlichen weißen Mäusen; DLSO berechnet nach Litchfield und Wilcoxon) racem. 2-Phenyl-3-methylmorpholin-H Cl ...... 88 mg/kg Maus s. c. D - 2 - Phenyl - 3 - methyl -morpholin-H Cl ...... 108 mg/kg Maus s. c. D-2-Phenyl-3,4-dimethylmorpholin-H Cl . . . . . . 510 mg/kg Maus s. c.The dextrorotatory tetrahydro-1,4-oxazines which can be prepared according to the invention are valuable medicaments which, for example, advantageously differ from the closest similar, racemic 2-phenyl-3-methyl-morpholine-H Cl. The progress achieved in this way is illustrated by the following comparisons 1. Acute toxicity (subcutaneous injection in male white mice; DLSO calculated according to Litchfield and Wilcoxon) racem. 2-phenyl-3-methylmorpholine-H Cl ...... 88 mg / kg mouse sc D - 2 - phenyl - 3 - methyl -morpholine-H Cl ...... 108 mg / kg mouse sc D- 2-phenyl-3,4-dimethylmorpholine-H Cl. . . . . . 510 mg / kg mouse sc

D - 2 - Phenyl - 3 - methyl -4-amyl-morpholin-H Cl 1480 mg/kg Maus s. c. 2: Wirkung auf die Spontanmotilität (Spontane Motilität von Mäusen angegeben in m Laüfstrecke/h) Kontrollen ohne Testsubstanz = normale mittlere Spontanmotilität der Kontrolltiere Spontan- normale Dosierung motilität mittlere Substanz in Lauf- Spontan- strecke/h motilität mg/kg m/h m/h racem. 2-Phenyl-3-me- thyl-morpholin-HCl 25 2,64 2,71 50 3,87 D-2-Phenyl- 3 -methyl- morpholin-HCl .... 25 3,96 2,71 50 5,81 racem. 2-Phenyl-3,4-di- methyl - morpholin - HCl .............. 20 2,5 2,35 40 3,1 D-2-Phenyl- 3,4 -dime- thyl-morpholin-HCl 20 2,7 2,35 40 3,15 D -2-Phenyl- 3 -methyl- 4 - amyl - morpholin - H Cl . . . . . . . . . . . . . . 50 1,72 2,71 100 2,03 Phenylisopropylamin (Benzedrin) ........ 3 8fache Spontan- motilität 3. Hungerdämpfender Effekt (im chronischen Fütterungsversuch nach Spengler, Waser und Brunckow an weiblichen weißen Wistaratten geprüft) EdSO = 50 °/o Hemmung in 30 Minuten racem. 2-Phenyl-3-methyl-morpholin-H Cl . . . . . . . . . . . . . . . . 18 mg/kg Ratte D-2-Phenyl-3-methyl-morpholin-H Cl . . . . . . . . . . . . . . . . . . . . . . 16 mg/kg Ratte D-2-Phenyl-3,4-dimethyl-morphohn-H Cl ... . . . . . . . . . . . . . 30 mg/kg Ratte D -2-Phenyl- 3 -methyl-4-amylmorpholin-H CI . . . . . . . . . . . . vorh., aber nicht exakt bestimmbar Von besonderer Bedeutung für den Vergleich des rechtsdrehenden 2-Phenyl-3-methyl-morpholin-HCl zum racemischen Chlorhydrat ist weiter, daß sich beide Verbindungen in ihrer Blutdruckwirkung nicht. unterscheiden. Die bessere Wirkung der rechtsdrehenden Verbindung auf Spontanmotilität und hungerdämpfenden Effekt ist daher anscheinend von der Blutdruckwirkung getrennt.D - 2 - phenyl - 3 - methyl -4-amyl-morpholine-H Cl 1480 mg / kg mouse sc 2: effect on spontaneous motility (spontaneous motility of mice given in m running distance / h) controls without test substance = normal mean spontaneous motility of the Control animals Spontaneously normal Dosage motility medium Substance in running spontaneous distance / h motility mg / kg m / hm / h racem. 2-phenyl-3-me- ethyl morpholine HCl 25 2.64 2.71 50 3.87 D-2-phenyl- 3 -methyl- morpholine HCl .... 25 3.96 2.71 50 5.81 racem. 2-phenyl-3,4-di- methyl - morpholine - HCl .............. 20 2.5 2.35 40 3.1 D-2-phenyl- 3,4 -dime- ethyl morpholine HCl 20 2.7 2.35 40 3.15 D -2-phenyl- 3 -methyl- 4 - amyl - morpholine - H Cl. . . . . . . . . . . . . . 50 1.72 2.71 100 2.03 Phenylisopropylamine (Amphetamines) ........ 3 8fold Spontaneous- motility 3. Hunger-suppressing effect (tested in the chronic feeding experiment according to Spengler, Waser and Brunckow on female white Wista rats) EdSO = 50% inhibition in 30 minutes of racem. 2-phenyl-3-methyl-morpholine-H Cl. . . . . . . . . . . . . . . . 18 mg / kg rat D-2-phenyl-3-methyl-morpholine-H Cl. . . . . . . . . . . . . . . . . . . . . . 16 mg / kg rat D-2-phenyl-3,4-dimethyl-morphohn-H Cl .... . . . . . . . . . . . . 30 mg / kg rat D -2-phenyl-3-methyl-4-amylmorpholine-H CI. . . . . . . . . . . . existing, but not exactly determinable. Of particular importance for the comparison of the dextrorotatory 2-phenyl-3-methyl-morpholine-HCl to the racemic chlorohydrate is that the blood pressure effect of the two compounds does not differ. differentiate. The better effect of the clockwise connection on spontaneous motility and the hunger-suppressing effect is therefore apparently separated from the effect of blood pressure.

` Wie die pharmakologischen Untersuchungen ergaben, besitzen die optisch aktiven rechtsdrehenden Morpholinverbindungen, bei geringster Toxizität die größte pharmakologische Wirksamkeit, z. B. benötigt man beim racemischen 2-Phenyl-3-methyl-morpholin-H Cl 1/5 der LDSO, um eine 50 °/oige Appetithemmung herbeizuführen, während man beim rechtsdrehenden (+) 2-Phenyl-3-methyl-morpholin-HCl schon mit 1/, der LDSO eine 50 °/oige Appetithemmung erhält. Die Herstellung der rechtsdrehenden Form des 2-Phenyl-3-methyl-morpholins und ihre ausschließliche therapeutische Anwendung unter Verzicht auf die belastende L-Form, wie sie im Racemat vorhanden ist, stellt also einen therapeutischen Fortschritt dar. Die am Stickstoff alkylierten, rechtsdrehenden Verbindungen (R2 = niedriges Alkyl) sind ebenfalls wirksamer als die Racemate. Sie haben eine noch geringere Toxizität und somit eine größere therapeutischeBreite. Schon mit 1/13bis 1/14 der Dosis LDSo wird eine 50 °/3ige Appetithemmung erreicht.`As the pharmacological tests showed, they have optical properties active dextrorotatory morpholine compounds, the greatest with the lowest toxicity pharmacological effectiveness, e.g. B. is required for racemic 2-phenyl-3-methyl-morpholine-H Cl 1/5 of the LDSO, in order to induce a 50% appetite suppression, while one is at the clockwise (+) 2-phenyl-3-methyl-morpholine-HCl already with 1 /, the LDSO one Preserves 50 per cent inhibition of appetite. The production of the dextrorotatory form of 2-phenyl-3-methyl-morpholine and their exclusive therapeutic use, renouncing the burdensome L-form, as it is present in the racemate, represents a therapeutic advance The dextrorotatory compounds alkylated on the nitrogen (R2 = low Alkyl) are also more effective than the racemates. You have an even lower one Toxicity and hence greater therapeutic breadth. Already with 1/13 to 1/14 of the LDSo dose 50% / 3% inhibition of appetite is achieved.

Beispiel 1 125 g linksdrehendes 1-Phenyl-2-(ß-oxyäthyl-methylamino)-propanol-(1), [a]" =-6' (in CH30H), werden unter Rühren in 125m1 Schwefelsäure (spez. Gew. = 1,840) eingetragen und 6 Stunden bei 90°C gerührt. Das Reaktionsprodukt wird auf Eis gegossen, mit 30 °/jger Natronlauge alkalisch gemacht und mit Äther extrahiert. Die Ätherlösung wird mit wenig gesättigter Kochsalzlösung gewaschen, über Natriumsulfat getrocknet, eingedunstet und der Rückstand einer fraktionierten Vakuumdestillation unterworfen. Beim Kp.a,5 mm = 82 bis 84°C geht die Base als farbloses, schwach viskoses Öl über (110,5 g) und dreht die Ebene des polarisierten Lichtes nach rechts: [a]D = -E-17,1° (in CH30H). Das hieraus hergestellte D-2-Phenyl-3,4-dimethyl-tetrahydro-1,4-oxazin-Hydrochlorid weist einen gleichen Drehungswert wie die Base auf.Example 1 125 g of levorotatory 1-phenyl-2- (ß-oxyethyl-methylamino) -propanol- (1), [a] " = -6 ' (in CH30H) are dissolved in 125 ml of sulfuric acid (spec. Wt. = 1,840) and stirred for 6 hours at 90 ° C. The reaction product is poured onto ice, made alkaline with 30 ° / jger sodium hydroxide solution and extracted with ether At a bp of 5 mm = 82 to 84 ° C. the base passes over as a colorless, slightly viscous oil (110.5 g) and turns the plane of polarized light to the right: [a] D = -E -17.1 ° (in CH30H) The D-2-phenyl-3,4-dimethyl-tetrahydro-1,4-oxazine hydrochloride produced from this has the same rotation value as the base.

Beispiel 2 35 g linksdrehendes 1-Phenyl-2-(ß-oxyäthylamino)-propanol-(1) [x]D = -7,7° werden in 35 ml Schwefelsäure, spezifisches Gewicht = 1,840, eingetragen und 2 Stunden auf 80°C erhitzt. Der gemäß dem Beispiel 1 erhaltene Rückstand destilliert beim Kp.o,5 mm = 80 bis 82°C schwach viskoses, farbloses Öl (30,2 g).Example 2 35 g of levorotatory 1-phenyl-2- (ß-oxyäthylamino) -propanol- (1) [x] D = -7.7 ° are entered in 35 ml of sulfuric acid, specific weight = 1.840 and heated to 80 ° C for 2 hours. The residue obtained according to Example 1 is distilled at bp 5 mm = 80 to 82 ° C, slightly viscous, colorless oil (30.2 g).

Optische Drehung der Base: [a]D = -E-22,2° (in CH30H). Optische Drehung des D-2-Phenyl-3-methyltetrahydro-1,4-oxazin-Hydrochlorids: [cc]D = -f-22,6° (in CH30H).Optical rotation of the base: [a] D = -E-22.2 ° (in CH30H). Optical rotation of D-2-phenyl-3-methyltetrahydro-1,4-oxazine hydrochloride: [cc] D = -f-22.6 ° (in CH30H).

Die Herstellung der Ausgangssubstanzen wird nicht beansprucht.The production of the starting substances is not claimed.

Claims (1)

PATENTANSPRUCH: Verfahren zur Herstellung von rechtsdrehenden, mehrfach substituierten Tetrahydro-1,4-oxazinen der allgemeinen Formel worin R1 einen niederen Alkylrest und R2 ein Wasserstoffatom oder einen niederen Alkylrest bedeuten, oder deren Salzen, dadurch gekennzeichnet, daß man linksdrehende Diäthanolamine der Formel worin R, und R2 die oben angegebene Bedeutung haben, in an sich bekannter Weise mit wasserabspaltenden Mitteln behandelt und gegebenenfalls anschließend nach üblichen Methoden in ihre Salze überführt. In Betracht gezogene Druckschriften: Deutsche Patentschriften Nr. 548 459, 587 586; Arch. exper. Path. u. Pharmakol., 222 [1954], S. 540 bis 554; Wiener med. Wschr., 105 [1955], S. 109 und 110.PATENT CLAIM: Process for the production of dextrorotatory, multiply substituted tetrahydro-1,4-oxazines of the general formula in which R1 is a lower alkyl radical and R2 is a hydrogen atom or a lower alkyl radical, or salts thereof, characterized in that levorotatory diethanolamines of the formula in which R 1 and R 2 have the meaning given above, treated in a manner known per se with dehydrating agents and, if appropriate, subsequently converted into their salts by customary methods. Considered publications: German Patent Specifications Nos. 548 459, 587 586; Arch. Exper. Path. and Pharmakol., 222 [1954], pp. 540 to 554; Viennese med. Wschr., 105 [1955], pp. 109 and 110.
DER17625A 1955-10-21 1955-10-21 Process for the preparation of dextrorotatory, multiply substituted tetrahydro-1,4-oxazines Pending DE1135464B (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011146850A1 (en) * 2010-05-21 2011-11-24 Research Triangle Institute Phenylmorpholines and analogues thereof
US8906908B2 (en) 2010-05-21 2014-12-09 Research Triangle Institute Hydroxybupropion analogues for treating drug dependence

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE548459C (en) * 1930-04-09 1932-04-13 Gustav Hildebrandt Dr Process for the preparation of 1-1-phenyl-2-methylaminopropan-1-ol
DE587586C (en) * 1930-06-26 1933-11-06 I G Farbenindustrie Akt Ges Process for the preparation of optically levorotatory 1-phenyl-2-aminopropanol- (1)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE548459C (en) * 1930-04-09 1932-04-13 Gustav Hildebrandt Dr Process for the preparation of 1-1-phenyl-2-methylaminopropan-1-ol
DE587586C (en) * 1930-06-26 1933-11-06 I G Farbenindustrie Akt Ges Process for the preparation of optically levorotatory 1-phenyl-2-aminopropanol- (1)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011146850A1 (en) * 2010-05-21 2011-11-24 Research Triangle Institute Phenylmorpholines and analogues thereof
US8906908B2 (en) 2010-05-21 2014-12-09 Research Triangle Institute Hydroxybupropion analogues for treating drug dependence
US9527823B2 (en) 2010-05-21 2016-12-27 Research Triangle Institute Hydroxybupropion analogues for treating drug dependence
US9617229B2 (en) 2010-05-21 2017-04-11 Research Triangle Institute Phenylmorpholines and analogues thereof

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