DE2605382C2 - Verfahren zur Herstellung von 2-p-Benzoylphenoxy-2-methylpropionsäureverbindungen - Google Patents

Verfahren zur Herstellung von 2-p-Benzoylphenoxy-2-methylpropionsäureverbindungen

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Publication number
DE2605382C2
DE2605382C2 DE2605382A DE2605382A DE2605382C2 DE 2605382 C2 DE2605382 C2 DE 2605382C2 DE 2605382 A DE2605382 A DE 2605382A DE 2605382 A DE2605382 A DE 2605382A DE 2605382 C2 DE2605382 C2 DE 2605382C2
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Germany
Prior art keywords
preparation
acetone
acid
benzoylphenoxy
chj
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DE2605382A
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DE2605382A1 (de
Inventor
André Lausanne Mieville
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Innophar Gesellschaft fur Pharmaforschung und Inn
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Caf Chemischer Arzneimittelvertrieb 6600 Saarbruecken De GmbH
Caf Chemischer Arzneimittelvertrieb 6600 Saarbruecken GmbH
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Priority claimed from GB5979/75A external-priority patent/GB1539897A/en
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Publication of DE2605382A1 publication Critical patent/DE2605382A1/de
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Publication of DE2605382C2 publication Critical patent/DE2605382C2/de
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
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    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • C07D213/67—2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
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  • Chemical & Material Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pyridine Compounds (AREA)
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Description

S A—CO-<1>— OH ΟΙ)
in der A die vorgenannte Bedeutung hat, mit Natriumhydroxid, Aceton und Chloroform zur entsp^vhenden Säure der allgemeinen Formel III
A-CO-ZV-O-CiCfti-COOH Π«)
in der A die vorgenannte Bedeutung hat, sowie gegebenenfalls Umsetzung dieser Säure mit einem Alkohol der allgemeinen Formel Y'OH, in der Y einen C] -Cjr Alkylrest bedeutet, dadurchgekennzeichnet, daß man 1 mol des p-Hydroxyhenzophcnos (II) mit 6 mol NaOH in 2 Liter Aceton unter Rückfluß zum entsprechenden Phenolat umsetzt, dann das erhaltene Gemisch unter Rückfluß mit einer Mischung aus 3 mol Chloroform und 0,583 Liter Aceton versetzt und den Rückfluß während 6 bis 8 Stunden nach beendeter Zugabe aufrechterhält, das gebildete NaCl abfiltriert, das Aceton imter vermindertem Druck abdampft und den Rückstand in möglichst wenig lauwarmen Wasser bei 350C löst, dann die wäßrige Phase gründlich mit
3C Dichloräthan wäscht und schließlich unter Kühlen mit HCl bis pH 1 unter Ausfällung der Säure (III) versetzt.
Die Erfindung betrifft ein Verfahren zur Herstellung von 2·p-Benzoylphenoxy·2·methyIρroρionsίureverbindung der allgemeinen Forsse!!
A-CO-(^ y— OC(CH3)I- COY
wobei Adie Bedeutung C6Hj, P-Cl6H4, Hi-ClC6H4,0-ClC6H4, P-BrC6H4,0-CH3C6H4, P-CH3OC6H4,3,4-Dichlorphenyl, 2,6-Dichlorphenyl, 2,6-Dimethylphenyl, 3,4,5-THmethoxyphenyl oder 4-Chlor-3-methoxyphenyl hat, und Y eine OH-Gruppe oder ein Ci -Qr Alkoxyrest ist
Die Verbindung der allgemeinen Formel I sind pharmakologisch aktiv und besitzen insbesondere kardiovaskuläre Aktivität als Arzneimittel gegen Hyperlipämie oder Hypercholesterinämie oder als Cholagoga.
Aus der DE-OS 22 50 327 ist ein Verfahren bekannt, nach welchem Verbindungen der allgemeinen Formel IV
R1 —C—f >—OH
wobei R1 - H, eine Alkylgruppe mit 1-5 C-Atomen oder eine Arylgruppe, vorzugsweise eine Phenyl- oder p-Chlorphenylgruppe ist, und R" und R1" ein Wasserstoff- oder Halogen-Atom, bevorzugt Cl, Br, F, eine Alkyl gruppe mit 1 -5 C-Atomen, CF3, SCH3, — SOCH3, — SO3CH3, — OCH3, — OH oder — C6Hj sind, mit einer Aceton-Chloroformmischung in alkalischem Medium zur Herstellung einer Verbindung der allgemeinen Formel V
CHj
R1—C—/yS—O—C-CO2H
R"1 CH3
umgesetzt werden.
Nach der für die Herstellung von p· (4-Chlorbenzoyl)-phenoxy-2-methyl-propionsäure angegebenen Arbeitsweise wird allgemein 1 mol einer Verbindung der Formel IV in wasserfreiem Aceton gelöst und 5 mol gepuiver-
tes Natriumhydroxid zugegeben, wobei das entsprechende Phenolat ausfallt Anschließend wird unter RückfluB erhitzt und 1,5 mol CHCl3 in wasserfreiem Aceton zugegeben. Nach Beendigung der Zugabe wird 10 Stunden unter Rückfluß erhitzt, nach dem Abkühlen Wasser zugesetzt und das Aceton verdampft Nach Waschen mit Äther wird die wäßrige Phase angesäuert, das Öl in Äther aufgenommen und mit einer Bicarbonatlösung extrahiert Durch Ansäuern der letzteren erhält man die gewünschte Säure in einer Ausbeute von 75 % (Fp. 185°C). s
Gegebenenfalls werden aus diesen Verbindungen durch Umsetzung mit einem Alkohol RIVOH die entsprechenden Ester hergestellt, wobei R™ — CH3, — C2H5 und i-C3H7 sein kann. Falls R' ein Arylrest ist, wird die Verbindung V zunächst mit SOCI2 oder PCIj in ein Säurechlorid umgewandelt, das man dann bei Bedarf mit einem Alkohol der Formel RIVOH zum Ester umsetzen kann.
Aufgabe der Erfindung ist es, ein neues Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I zur Verfügung zu stellen, wobei A die Bedeutung C6H5, P-ClC6H4, In-ClC6H4, 0-ClC6H4, P-BrC6H4, 0-CH3C6H4, D-CH3OC6H4, 3,4-Dichlorphecyl, 2,6-Dichlorphenyl, 2,6-DimethylphenyL 3,4,5-Trimethoxyphenyl oder i-Chlor-S-methoxyphenyl hat, und Y eine OH-Gruppe oder ein C1-Ci2-Alkoxyrest ist, bei dem man ein p-Hydroxybenzophenon der allgemeinen Formel Π
15
A-CO-ΛΛ-ΟΗ
in der A die Bedeutung wie in Formel I hat, mit Natriumhydroxid in Aceton und Chloroform zur entsprechenden Säure der allgemeinen Formel ΠΙ
umsetzt, wobei A die vorstehende Bedeutung hat, sowie gegebenenfalls diese Säure mit einem Alkanol der allgemeinen Formel Y'OH verestert, wobei Y eine C1-C)2 Alkylgruppe darsteU*.
Das Verfahren ist dadurch gekennzeichnet, daß man 1 mol des p-Hydroxybenzophenons II mit 6 mol NaOH in 2 Liter Aceton unter Rückfluß zum entsprechenden Phenolat umsetzt, dann das erhaltene Gemisch unter Rückfluß mit einer Mischung aus 3 mol Chloroform und 0,583 Liter Aceton versetzt und den Rückfluß während 6 bis 8 Stunden nach beendeter Zugabe aufrechterhält, das gebildete NaCI abfiltriert, das Aceton unter vermindertem Druck abdampft und den Rückstand in möglichst wenig lauwarmem Wasser bei 35°C löst dann die wäßrige Phase gründlich mit Dict!oräth£~ wäscht und schließlich unter Kühlen mit HCl bis pH 1 unter Ausfällung der Säure III versetzt.
Gegenüber dem in der DE-OS ?"'5O 327 beschriebenen Verfahren zeichnet sich das erfindungsgemäße Verfahren durch eine kürzere Reaktionszeit und eine einfachere Verfahrensweise aus. Darüberhinaus wird nach dem erfindungsgemäßen Verfahren ein Produkt mit einem hohen Reinheitsgrad erhalten, wie Vergieichsversuche gezeigt haben. So erhält man nach dem erfindungsgemäßen Verfahren die Verbindung 5 der nachstehenden Tabelle in einer Ausbeute von 80% und einer Reinheit von 99,8%, während das Verfahren der DE-OS 22 50 327 nur eine Ausbeute von 75 % liefert und das Produkt nur einen Reinheitsgrad von 9J.",'* aufweist.
40
Beispiel
Herstellung von 2-[4-(p-Chlorbenzoyl)-phenoxy]-2-methyl-propionsäure
45
Ein 20 Liter fassender Kolben wird mit 12 Liter wasserfreiem Aceton 1,395 kg (6 mol) 4'-Chlor-4-hydroxybenzophenon und 1,44 kg (36 mol) Ätznatron beschickt. Nachdem man die Mischung 2 Stunden unter Rückfluß gehalten hat (zur Bildung des Phenolats), versetzt man sofort, bei abgeschalteter Heizung, mit dem Gemisch: 2,16 kg (18 mol) Chloroform, verdünnt mit 3,5 Liter Aceton.
Die Zugabe ist ausreichend, um den Rückfluß aufrechtzuerhalten, der auf diese Weise mindestens 6 Stunden dauert. Dann (es bleibt noch 1 /4 des Gemisches zuzusetzen) läßt die exotherme Reaktion nach. Man schaltet die Heizung wieder an, so daß der Rückfluß während 6 bis 8 Stunden nach beendeter Zugabe aufrechterhalten bleibt. Dann läßt man abkühlen, filtriert vom abgeschiedenen Natriumchlorid (das Natriumsalz der gewünschten Säure bleibt im Aceton gelöst) und dampft das Aceton unter vermindertem Druck ab. Nachdem man den Rückstand in möglichst wenig lauwarmem Wasser (etwa 35 °C) gelöst hat, wird die wäßrige Phase gründlich (drei- bis viermal) mit Dichloräthan gewaschen und dann unter Kühlen mit HCl bis pH 1 versetzt. Hierbei scheidet sich die Säure ab. Nachdem man 30 Minuten kräftig gerührt hat, wird die Säure zentrifugiert, gründlich mit Wasser gewaschen und dann getrocknet. Man erhält 1,61 kg (85%) vom F. 1820C.
Diese Säure enthält Spuren (3 bis 4 Prozent) nicht umgesetztes Phenol; alle anderen Verunreinigungen sind durch die beschriebene einfache Behandlung entfernt worden, Eine Reinigung dieser Säure mittels Natriumhydrogencarbonat (die technisch sehr vorteilhaft ist) erweist sich als völlig unnötig. Um die Säure als solche rein zu erhalten, kristallisiert man sie aus Toluol um F. 185°C.
Die nachfolgende Tabelle enthält eine Aufstellung der Säuren und der daraus hergestellten entsprechenden Ester, die nach dem erfindungsgemäßen Verfahren hergestellt wurden.
TabeUe
Verbindungen der allgemeinen Formel I, die nach dem erfindungsgemäßen Verfahren hergestellt wurden
Verbindung
F. ("C) falls nichts anderes angegeben
130
OCH3
OC2H5
CH3
/ — O—CH
\ OH
CH3
58
87
84
185
10 11
12
13 14 15
Cl
Cl
OCH3 OC2H5
CH,
— OCH
CH3
— O — CH C7H14
— O — C12H23
-0-C1H17
CH3
OCH
C2H5 OC(CH3),
-0-CH(C2H5)J
< - 1,535
-OCH(CH3)CH2CH2CH3 55
Foitsetzung
Verbindung
16
18
20
21 22 23 24
25 26 27 28 29
Cl
Cl
Bi
CH3
— Ο —CH
\
CHj
CH3
CH3
— Ο —CH
C2H5
— Ο —CH(CHj)CH2CHj
— Ο —C1H17
— Ο—
CH3
— Ο—CH
CH3
Ο—CbH25
Ο—CH(CH3)C2Hj
OH
F. ("C) falls nichts anderes angegeben
121
114
182
38
129
144
74
155
Fortsetzung
Verbindung A Y F. (0C)
falls nichts
anderes
angegeben
Cl
Cl
Cl Cl
Cl
CH3
HjCO HjCO HjCO
H3CO H3CO H3CO
H3CO
H3CO
— O —CH \
CHj
CHj
OH
— O—CH \
CHj
CHj
OCH(CHj)2
OCH(CHj)2

Claims (1)

  1. Patentanspruch:
    Verfahren zur Herstellung von2-p-Benzoylphenoxy-2-methylpropionsäureverbindungen der allgemeinen Formell s
    A—CO—/^S-OC(CHj)1—CO—Y (D
    in der A die Bedeutung C6H,, P-Cl6H4, Bi-ClC6H4,0-ClC6H4, P-BrC6H4,0-CH3C6H4, P-CH3OC6H4,3,4-DichlorphenyL 2,6-Dicblorphenyl, 2,6-Dimethylphenyl, 3,4,5-Trimethoxyphenyl oder 4-Chlor-3-methoxyphe- nyl hat, und Y eine OH-Gruppe oder ein Q-Qr Alkoxyrest ist, durch Umsetzung eines p-Hydroxybenzophenons der allgemeinen Formel Π
DE2605382A 1975-02-12 1976-02-11 Verfahren zur Herstellung von 2-p-Benzoylphenoxy-2-methylpropionsäureverbindungen Expired DE2605382C2 (de)

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GB5979/75A GB1539897A (en) 1975-02-12 1975-02-12 Phenoxypropionic acid derivatives
GB5063075 1975-12-10

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AR223305A1 (es) 1981-08-14
DE2605382A1 (de) 1976-08-26
SE447651B (sv) 1986-12-01
CH620415A5 (de) 1980-11-28
NO760440L (de) 1976-08-13
CH617657A5 (de) 1980-06-13
IE43078L (en) 1976-08-12
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AU1105376A (en) 1977-08-18
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FR2342723B1 (de) 1981-05-29
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CA1069523A (en) 1980-01-08
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