CH229084A - Process for the preparation of the monophosphoric acid ester of 3,3'-methylene-bis-4,4'-oxy-coumarin. - Google Patents

Process for the preparation of the monophosphoric acid ester of 3,3'-methylene-bis-4,4'-oxy-coumarin.

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Publication number
CH229084A
CH229084A CH229084DA CH229084A CH 229084 A CH229084 A CH 229084A CH 229084D A CH229084D A CH 229084DA CH 229084 A CH229084 A CH 229084A
Authority
CH
Switzerland
Prior art keywords
sep
bis
oxy
coumarin
acid ester
Prior art date
Application number
Other languages
German (de)
Inventor
F Hoffmann- Aktiengesellschaft
Original Assignee
Hoffmann La Roche
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 Hoffmann La Roche filed Critical Hoffmann La Roche
Publication of CH229084A publication Critical patent/CH229084A/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

  

  Verfahren zur     Darstellung    des     blono-phosphorsäureesters    des     3,3'-biethylen-          bis-4,4'-ogy-cumarins.     
EMI0001.0005     
  
    Link <SEP> und <SEP> Mitarbeiter <SEP> (Journal <SEP> of <SEP> Biol.
<tb>  Chemistry <SEP> 138 <SEP> [1941], <SEP> S.21; <SEP> 136 <SEP> [1940],
<tb>  S. <SEP> 47; <SEP> 13.8 <SEP> [19411, <SEP> .S. <SEP> 513; <SEP> 13<B>8</B> <SEP> [1941],
<tb>  S. <SEP> 1) <SEP> haben <SEP> aus <SEP> faulem. <SEP> Klee <SEP> einen <SEP> Faktor <SEP> ge  wonnen, <SEP> der <SEP> bei <SEP> Tieren <SEP> schwere <SEP> haemorrha"-i.

    sche <SEP> Zustände <SEP> auslöste. <SEP> Die <SEP> nähere <SEP> Unter  suchung,der <SEP> Verbindung <SEP> ergab, <SEP> dass <SEP> das <SEP> 3,3'  ilIethylen-bi@s-4,4'-ogy-.cumarin <SEP> (Annalen <SEP> der
<tb>  Chemie <SEP> 367 <SEP> [1909], <SEP> S.169) <SEP> der <SEP> folgenden
<tb>  Formel     
EMI0001.0006     
    vorliegt.

   Weitere     Versuche        zeigten,    dass das       3,3'-Methylen-bi9-4,4'-ogy-,cumarin    bei Mensch       und    Tier     den,        Prothrombinspiegel    des Blutes  stark     senkt.    Die     Verabreichung    der     Verbin.-          d:ung:

      erfolgte bei Menschen ausschliesslich  per os, bei Tieren per     os    sowie     parenteral    in  
EMI0001.0019     
  
    Form <SEP> des <SEP> Natriumsalzes. <SEP> Für <SEP> die <SEP> Therapie
<tb>  beim <SEP> Menschen <SEP> scheidet <SEP> die <SEP> Verabreichung
<tb>  dies <SEP> Natriumsalzes <SEP> aus, <SEP> da <SEP> dieses <SEP> nur <SEP> in <SEP> stark
<tb>  alkalischer <SEP> Lösung <SEP> (p$ <SEP> = <SEP> ,ca. <SEP> 11) <SEP> löslich <SEP> ist.
<tb>  



  Es <SEP> wurde <SEP> nun <SEP> ,gefunden, <SEP> -dass <SEP> man <SEP> zu
<tb>  leicht <SEP> wasserlöslichen <SEP> Abkömmlingen <SEP> des <SEP> 3,3'  Methylen-bis-4,4'-ogy-eumarins <SEP> und <SEP> dessen
<tb>  Substitutionsprodukten <SEP> gelangt, <SEP> wenn <SEP> man
<tb>  diese <SEP> Verbindungen <SEP> mit <SEP> Phosphorogychlo@rid
<tb>  verestert <SEP> und, <SEP> das <SEP> Reaktionsprodukt <SEP> mit <SEP> einer
<tb>  Base <SEP> umsetzt.
<tb>  



  Di,e <SEP> Veresterung <SEP> der <SEP> Ogygruppe,des <SEP> 3,3=
<tb>  Methylen-bi:s-4,4'-ogy-cumarins <SEP> verl@äult <SEP> nicht
<tb>  immer <SEP> in <SEP> ,gleicher <SEP> Weise. <SEP> So <SEP> erhält <SEP> man <SEP> bei
<tb>  .der <SEP> Einwirkung <SEP> von <SEP> Essigsäureanhydrid <SEP> und
<tb>  Pyridin <SEP> eine <SEP> Verbindung, <SEP> Jeren <SEP> Analysen  werte <SEP> auf <SEP> einen <SEP> intramolekulanen <SEP> oder <SEP> dimole  kularen <SEP> Äther <SEP> Mimmen. <SEP> Auch <SEP> bei <SEP> _der <SEP> Dar  ,Stellung <SEP> des <SEP> Pho <SEP> phorsäureasters <SEP> zeigen <SEP> sich
<tb>  Schwierigkeiten. <SEP> .So <SEP> wurden <SEP> zunächst <SEP> Ver  bindungen <SEP> gewonnen, <SEP> die <SEP> keinen <SEP> Phosphor
<tb>  enthielten.

   <SEP> Erst <SEP> bei <SEP> Einhaltung <SEP> von <SEP> schonen-         den     Bedingungen    bei den Umsetzungen wird  ein     Pho@sphorsäureester    in     guter    Ausbeute er  halten.     Zweckmä.Big    hat sich die Zugabe eines       säurebindenden    Mittels., insbesondere einer  tertiären     orb        ,nischen    Base, wie     Pyridin,        Di:-          msethylanilin,        erwiesen.     



  Gegenstand des vorliegenden     Patentes    ist  ein Verfahren zur Darstellung des     Mono-          phosphorsäureesters    des     3,3'-1Methylen    -bis     -          4,4'-oxy-cumarins,    welches dadurch     gekenn-          zei:

  chnet    ist,     dass    man     3,3'-blethylen-bis-4,4'-          oxy-aumarin    mit     Phosphoroxyehlorid        ver-          estert.    Zweckmässig verwendet man einen       Überschuss    von     Phospho-roxychlorid    und setzt  ein     säurebindendes        Mittel    zu.  



  Der Mono -     phosphorsäureester    des     U'-          Methylen-bis-4,4'-oxy,cumarins    schmilzt bei       238-240 .    Er ist     wasserlöslich;    die Lösun  gen seiner     Alkalisalze    sind kochbeständig.  Die neue Verbindung soll als     Arzneimittel     verwendet werden.  



  <I>Beispiel:</I>  6,8 Teile     3,3'-Methylen-bis-4,4'-oxycuma-          rin,    werden in 7,4 Raumteilen     Dimethylanilin     und 24 Raumteilen     abs.        Toluol    mit 7.2     Raum-          teilen        Phosphoroxychlorid        während.    1     Stunde     bei     +    5  versetzt und 24 Stunden bei     Zim-          mertemperatur    gerührt.

   Die     Kristallmasse          wird    unter     Feuchtigkeitsausschluss    abgesaugt,  mit     abs.        Toluol        nachgewaschen    und in    210 Raumteilen Wasser, die     die        berechnete     Menge     Natriumhy        droxyd    enthalten, unter  Kühlung gelöst. Das     Natriumsalz    wird nach       Einerogen    der Lösung im Vakuum bei 40   isoliert.

   Die wässerige Lösung des     Natrium-          salzes    wird mit konzentrierter     Salzsäure    an  gesäuert und der ausfallende Phosphorsäure  eister bei 0  abgesaugt. Man erhält eine fast       quantitative        Ausbeute.  



  Process for the preparation of the blono-phosphoric acid ester of 3,3'-bidhylene-bis-4,4'-ogy-coumarin.
EMI0001.0005
  
    Link <SEP> and <SEP> employees <SEP> (Journal <SEP> of <SEP> Biol.
<tb> Chemistry <SEP> 138 <SEP> [1941], <SEP> p.21; <SEP> 136 <SEP> [1940],
<tb> S. <SEP> 47; <SEP> 13.8 <SEP> [19411, <SEP> .S. <SEP> 513; <SEP> 13 <B> 8 </B> <SEP> [1941],
<tb> S. <SEP> 1) <SEP> have <SEP> from <SEP> lazy. <SEP> Klee <SEP> gained a <SEP> factor <SEP>, <SEP> the <SEP> in <SEP> animals <SEP> severe <SEP> haemorrha "-i.

    cal <SEP> states <SEP> triggered. <SEP> The <SEP> closer <SEP> investigation, the <SEP> connection <SEP> showed <SEP> that <SEP> the <SEP> 3,3 'ilIethylene-bi @ s-4,4'- ogy-.coumarin <SEP> (Annals <SEP> of the
<tb> Chemistry <SEP> 367 <SEP> [1909], <SEP> p.169) <SEP> of the <SEP> following
<tb> formula
EMI0001.0006
    present.

   Further experiments showed that the 3,3'-methylene-bi9-4,4'-ogy-, coumarin in humans and animals greatly lowers the prothrombin level in the blood. The administration of the compound:

      was carried out per os in humans, per os in animals and parenterally in
EMI0001.0019
  
    Form <SEP> of the <SEP> sodium salt. <SEP> For <SEP> the <SEP> therapy
<tb> with <SEP> humans <SEP> <SEP> separates the <SEP> administration
<tb> this <SEP> sodium salt <SEP> from, <SEP> because <SEP> this <SEP> only <SEP> in <SEP> strong
<tb> alkaline <SEP> solution <SEP> (p $ <SEP> = <SEP>, approx. <SEP> 11) <SEP> is soluble <SEP>.
<tb>



  <SEP> was found <SEP> now <SEP>, <SEP> -that <SEP> man <SEP> to
<tb> easily <SEP> water-soluble <SEP> descendants <SEP> of <SEP> 3,3 'methylenebis-4,4'-ogy-eumarins <SEP> and <SEP> thereof
<tb> Substitution products <SEP> arrives, <SEP> if <SEP> man
<tb> these <SEP> compounds <SEP> with <SEP> Phosphorogychlo @ rid
<tb> esterifies <SEP> and, <SEP> the <SEP> reaction product <SEP> with <SEP> one
<tb> Base <SEP> implements.
<tb>



  Di, e <SEP> esterification <SEP> of the <SEP> ogy group, of the <SEP> 3,3 =
<tb> Methylen-bi: s-4,4'-ogy-coumarins <SEP> does not leave <SEP>
<tb> always <SEP> in <SEP>, same <SEP> way. <SEP> So <SEP> <SEP> you get <SEP> at
<tb> .the <SEP> action <SEP> of <SEP> acetic anhydride <SEP> and
<tb> Pyridine <SEP> a <SEP> compound, <SEP> Jeren <SEP> analyzes value <SEP> on <SEP> a <SEP> intramolecular <SEP> or <SEP> dimolecular <SEP> ether <SEP> Mimmen. <SEP> Also <SEP> with <SEP> _der <SEP> Dar, position <SEP> of <SEP> Pho <SEP> phosphoric acid ester <SEP> show <SEP>
<tb> difficulties. <SEP>. So <SEP> <SEP> were initially <SEP> compounds <SEP> obtained, <SEP> the <SEP> no <SEP> phosphorus
<tb> contained.

   <SEP> Only <SEP> if <SEP> compliance with <SEP> and <SEP> gentle conditions during the reactions will a phosphoric acid ester be obtained in good yield. The addition of an acid-binding agent, in particular a tertiary orbic base, such as pyridine, di-methylaniline, has proven to be useful.



  The subject of the present patent is a process for the preparation of the monophosphoric acid ester of 3,3'-1-methylene-bis-4,4'-oxy-coumarin, which is characterized by:

  What is known is that 3,3'-blethylene-bis-4,4'-oxy-aumarin is esterified with phosphorus oxychloride. It is advisable to use an excess of phospho-oxychloride and to add an acid-binding agent.



  The monophosphoric acid ester of U'-methylene-bis-4,4'-oxy, coumarin melts at 238-240. It is soluble in water; the solutions of its alkali salts are resistant to boiling. The new compound is intended to be used as a medicine.



  <I> Example: </I> 6.8 parts of 3,3'-methylene-bis-4,4'-oxycumarine, in 7.4 parts by volume of dimethylaniline and 24 parts by volume of abs. Toluene with 7.2 parts by volume of phosphorus oxychloride during. Added 1 hour at +5 and stirred for 24 hours at room temperature.

   The crystal mass is suctioned off with exclusion of moisture, with abs. Washed toluene and dissolved in 210 parts by volume of water containing the calculated amount of sodium hydroxide, with cooling. The sodium salt is isolated after extracting the solution in vacuo at 40.

   The aqueous solution of the sodium salt is acidified with concentrated hydrochloric acid and the phosphoric acid which precipitates is suctioned off at 0. An almost quantitative yield is obtained.

Claims (1)

PATENTANSPRUCH: Verfahren zur Darstellung des Mono- ph.osphorsäureesters dies 3,3'-31ethylen -bis - 4,4'-oxy-cumarins, dadurch gekennzeichnet, dass man 3,3'-1llethyl,cn-bis-4,4'-oxy-cumarin mit Phosphoroxychlorid verestert. Der l@lono-phosphorsä.wrees:ter des U'-Me:- thylen-bis-4,4'-oxy-c.umarins schmilzt bei 238 bis 240 . PATENT CLAIM: Process for the preparation of the monophosphoric acid ester this 3,3'-31ethylene-bis-4,4'-oxy-coumarins, characterized in that 3,3'-1llethyl, cn-bis-4,4 ' -oxy-coumarin esterified with phosphorus oxychloride. The l@lono-phosphorsä.wrees: ter of the U'-Me: -thylen-bis-4,4'-oxy-c.umarins melts at 238 to 240. Er ist wasserlöslich; die Lösungen seiner Alkabbalze sind kochbeständig. UNTERANSPRUCH: Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass man 3,3'-DTethylen-bis- 4,4'-oxy-cuimar,n mit übersehüssig,em Pho@s- phoroxyehlorid in Gegenwart eines säurebin denden 3littels versetzt. It is soluble in water; the solutions of his Alkabbalze are resistant to boiling. SUBSTANTIAL CLAIM: Process according to claim, characterized in that 3,3'-DTethylene-bis-4,4'-oxy-cuimar, n is mixed with excess phosphorus-phoroxychloride in the presence of an acid-binding agent.
CH229084D 1942-06-09 1942-06-09 Process for the preparation of the monophosphoric acid ester of 3,3'-methylene-bis-4,4'-oxy-coumarin. CH229084A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CH229084T 1942-06-09

Publications (1)

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CH229084A true CH229084A (en) 1943-09-30

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CH229084D CH229084A (en) 1942-06-09 1942-06-09 Process for the preparation of the monophosphoric acid ester of 3,3'-methylene-bis-4,4'-oxy-coumarin.

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BE (1) BE449545A (en)
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