CH670084A5 - Prodn. of antiinflammatory 4-naphthyl-2-butanone deriv. - Google Patents

Prodn. of antiinflammatory 4-naphthyl-2-butanone deriv. Download PDF

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Publication number
CH670084A5
CH670084A5 CH53687A CH53687A CH670084A5 CH 670084 A5 CH670084 A5 CH 670084A5 CH 53687 A CH53687 A CH 53687A CH 53687 A CH53687 A CH 53687A CH 670084 A5 CH670084 A5 CH 670084A5
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CH
Switzerland
Prior art keywords
formula
compound
iii
naphthyl
reaction
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Application number
CH53687A
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German (de)
Inventor
Richard Keith Anderson
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Beecham Group Plc
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Publication date
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Publication of CH670084A5 publication Critical patent/CH670084A5/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/72—Hydrazones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/516—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of nitrogen-containing compounds to >C = O groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

Prodn. of 4-(6-methoxy-2-naphthyl)- 2-butanone of formula (I) is effected by (a) reacting a 6-methoxy-2-naphthylmethyl halide of formula (II) with an alkali metal acetone hydrazone of formula (III), and (b) subjecting the prod. of formula (IV) to acid hydrolysis: In the formula, X=halogen; M=alkali metal; R1 and R2=1-6C alkyl.

Description

       

  
 



   BESCHREIBUNG



   Diese Erfindung bezieht sich auf ein Verfahren zur Herstellung von 4-(6-Methoxy-2-naphthyl)-butan-2-on und auf Zwischenprodukte, die bei dieser Synthese brauchbar sind.



   Die US-Patentschrift 4 061 779 beschreibt 4-(6-Methoxy-2- naphthyl)-butan-2-on (Nabumetone) und dessen Verwendung bei der Behandlung von rheumatischen und arthritischen Affektionen. Eine Anzahl von Verfahren zur Herstellung der Verbindung sind ebenfalls beschrieben. Die US-Patentschriften 4 221 741 und 4 247 709 beschreiben weitere Verfahren zur Herstellung von Nabumetone.



   Ein weiteres Verfahren zur Herstellung von Nabumetone wurde nun erfunden, welches Verfahren durch die Bildung eines Hydrazons, gefolgt von Hydrolyse, gekennzeichnet ist.



   Demgemäss bezieht sich die vorliegende Erfindung auf ein Verfahren zur Herstellung von 4-(6-Methoxy-2-naphthyl)- butan-2-on, das gekennzeichnet ist durch die Reaktion einer Verbindung der Formel (I):
EMI1.5     
 worin Hal Halogen ist, mit einer Verbindung der Formel   (II)   
EMI1.6     
 worin M ein Alkalimetall ist und   R1    und R2 Alkyl mit 1 bis 6 Kohlenstoffatomen sind, gefolgt von saurer Hydrolyse.



   Hal ist vorzugsweise Chlor, und M ist vorzugsweise Lithium. R1 und R2 sind vorzugsweise beide Methyl.



   Die Reaktion findet in einem inerten Lösungsmittel, wie Tetrahydrofuran, bei Umgebungstemperatur statt.



   Die Reaktion verläuft über ein Zwischenprodukt der Formel (III):
EMI1.7     

Die anschliessende Hydrolyse der Verbindungen der Formel (III) findet unter sauren Bedingungen, z.B. unter Verwendung von Salzsäure/Wasser, bei Umgebungstemperaturen, z.B. 20 bis 30   "C,    statt.

 

   Die Verbindung der Formel (II) wird zweckmässig in situ aus Aceton und N,N-Dimethylhydrazin hergestellt.



   Verbindungen der Formel (I) sind bekannt.



   Verbindungen der Formel (III) sind neu und bilden einen Gegenstand der vorliegenden Erfindung.



   Das folgende Beispiel erläutert die Erfindung.  



  Beispiel
EMI2.1     

Das Hydrazon (2) wurde aus 2-Chlormethyl-6-methoxynaphthalin und dem Lithio-N,N-dimethylhydrazon von Aceton, das in situ hergestellt wurde [siehe Yamashita et. al., Bull. Chem. Soc. Jpn. 58, 407408 (1985)], hergestellt und quantitativ als Ol erhalten.



   Das Hydrazon (2) wurde bei Raumtemperatur mit 5-molarer Salzsäure behandelt und ergab das Produkt (3) in 95%iger Ausbeute mit einer Reinheit von 80% (Reinheitsausbeute 76%). 



  
 



   DESCRIPTION



   This invention relates to a process for the preparation of 4- (6-methoxy-2-naphthyl) butan-2-one and intermediates useful in this synthesis.



   U.S. Patent 4,061,779 describes 4- (6-methoxy-2-naphthyl) -butan-2-one (nabumetone) and its use in the treatment of rheumatic and arthritic disorders. A number of methods of making the compound are also described. U.S. Patents 4,221,741 and 4,247,709 describe other processes for making nabumetones.



   Another process for the preparation of nabumetone has now been invented, which process is characterized by the formation of a hydrazone followed by hydrolysis.



   Accordingly, the present invention relates to a process for the preparation of 4- (6-methoxy-2-naphthyl) butan-2-one, which is characterized by the reaction of a compound of the formula (I):
EMI1.5
 wherein Hal is halogen, with a compound of formula (II)
EMI1.6
 wherein M is an alkali metal and R1 and R2 are alkyl of 1 to 6 carbon atoms, followed by acid hydrolysis.



   Hal is preferably chlorine and M is preferably lithium. R1 and R2 are preferably both methyl.



   The reaction takes place in an inert solvent such as tetrahydrofuran at ambient temperature.



   The reaction proceeds via an intermediate of formula (III):
EMI1.7

The subsequent hydrolysis of the compounds of formula (III) takes place under acidic conditions, e.g. using hydrochloric acid / water, at ambient temperatures, e.g. 20 to 30 "C instead.

 

   The compound of formula (II) is conveniently prepared in situ from acetone and N, N-dimethylhydrazine.



   Compounds of formula (I) are known.



   Compounds of formula (III) are new and form an object of the present invention.



   The following example illustrates the invention.



  example
EMI2.1

The hydrazone (2) was derived from 2-chloromethyl-6-methoxynaphthalene and the lithio-N, N-dimethylhydrazone of acetone, which was prepared in situ [see Yamashita et. al., Bull. Chem. Soc. Jpn. 58, 407408 (1985)], prepared and quantitatively obtained as an oil.



   The hydrazone (2) was treated with 5 molar hydrochloric acid at room temperature and gave the product (3) in 95% yield with a purity of 80% (purity yield 76%).

Claims (10)

PATENTANSPRÜCHE 1. Verfahren zur Herstellung von 4-(6-Methoxy-2-naphthyl)-butan-2-on, gekennzeichnet durch die Reaktion einer Verbindung der Formel (I): EMI1.1 worin Hal Halogen ist, mit einer Verbindung der Formel aI) EMI1. PATENT CLAIMS 1. A process for the preparation of 4- (6-methoxy-2-naphthyl) -butan-2-one, characterized by the reaction of a compound of the formula (I): EMI1.1  wherein Hal is halogen, with a compound of the formula aI) EMI1. 2 worin M ein Alkalimetall ist und R1 und R2 Alkyl mit 1 bis 6 Kohlenstoffatomen sind, gefolgt von saurer Hydrolyse der als Zwischenprodukt gebildeten Verbindung der Formel (III): EMI1.3 2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, dass Hal in Formel (I) Chlor ist. 2nd  wherein M is an alkali metal and R1 and R2 are alkyl of 1 to 6 carbon atoms, followed by acidic hydrolysis of the intermediate compound of formula (III): EMI1.3 2. The method according to claim 1, characterized in that Hal in formula (I) is chlorine. 3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, dass M in Formel (II) Lithium ist.  3. The method according to claim 1 or 2, characterized in that M in formula (II) is lithium. 4. Verfahren nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, dass R1 und R2 Methyl bedeuten.  4. The method according to any one of claims 1 to 3, characterized in that R1 and R2 are methyl. 5. Verfahren nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, dass man die Reaktion einer Verbindung der Formel (I) mit einer Verbindung der Formel (II) in einem inerten organischen Lösungsmittel ausführt.  5. The method according to any one of claims 1 to 4, characterized in that one carries out the reaction of a compound of formula (I) with a compound of formula (II) in an inert organic solvent. 6. Verfahren nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass man die Reaktion einer Verbindung der Formel (I) mit einer Verbindung der Formel (II) bei Umgebungstemperatur ausführt.  6. The method according to any one of claims 1 to 5, characterized in that one carries out the reaction of a compound of formula (I) with a compound of formula (II) at ambient temperature. 7. Verfahren nach einem der Ansprüche 1 bis 5, dadurch gekennzeichnet, dass man die saure Hydrolyse der als Zwischenprodukt gebildeten Verbindung der Formel (III) in wässriger Salzsäure ausführt.  7. The method according to any one of claims 1 to 5, characterized in that one carries out the acidic hydrolysis of the intermediate compound of formula (III) in aqueous hydrochloric acid.   8. Verfahren nach Anspruch 7, dadurch gekennzeichnet, dass man die saure Hydrolyse der als Zwischenprodukt gebildeten Verbindung der Formel (III) bei einer Temperatur von 20 "C bis 30 "C ausführt.  8. The method according to claim 7, characterized in that one carries out the acidic hydrolysis of the intermediate compound of formula (III) at a temperature of 20 "C to 30" C. 9. Verfahren nach Anspruch 1, gekennzeichnet durch die Reaktion einer Verbindung der Formel (I), worin Hal Chlor bedeutet, mit einer Verbindung der Formel (II), worin M für Lithium steht und R1 und R2 Methyl bedeuten, gefolgt von saurer Hydrolyse der als Zwischenprodukt gebildeten Verbindung der Formel (III) in wässriger Salzsäure, wobei die Verbindungen der Formeln (I), (II) und (III) wie in An spruch 1 definiert sind.  9. The method according to claim 1, characterized by the reaction of a compound of formula (I), in which Hal is chlorine, with a compound of formula (II), in which M is lithium and R1 and R2 are methyl, followed by acid hydrolysis of Compound of the formula (III) formed as an intermediate in aqueous hydrochloric acid, the compounds of the formulas (I), (II) and (III) as defined in claim 1. 10. Verbindung der Formel (III): EMI1.4 worin R1 und R2 Methyl bedeuten, als Zwischenprodukt im Verfahren nach Anspruch 1.  10. Compound of formula (III): EMI1.4  wherein R1 and R2 are methyl, as an intermediate in the process according to claim 1.
CH53687A 1986-02-15 1987-02-13 Prodn. of antiinflammatory 4-naphthyl-2-butanone deriv. CH670084A5 (en)

Applications Claiming Priority (1)

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GB868603778A GB8603778D0 (en) 1986-02-15 1986-02-15 Chemical process

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CH670084A5 true CH670084A5 (en) 1989-05-12

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JP (1) JPS62195344A (en)
CH (1) CH670084A5 (en)
DK (1) DK75487A (en)
ES (1) ES2004879A6 (en)
GB (1) GB8603778D0 (en)
GR (1) GR870258B (en)
NL (1) NL8700358A (en)
SE (1) SE465926B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0361067A1 (en) * 1988-09-01 1990-04-04 Bayer Ag Disubstituted naphthalines, preparation processes and their herbicidal use
EP2860169A3 (en) * 2009-04-17 2015-10-21 Centro De Neurociencias De Cuba Method for obtaining novel derivatives of naphtalene for the in vivo diagnosis of Alzheimer's disease

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4943579A (en) * 1987-10-06 1990-07-24 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services Water soluble prodrugs of camptothecin
US5756851A (en) * 1996-10-21 1998-05-26 Albemarle Corporation Production of nabumetone or precursors thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0361067A1 (en) * 1988-09-01 1990-04-04 Bayer Ag Disubstituted naphthalines, preparation processes and their herbicidal use
US5108489A (en) * 1988-09-01 1992-04-28 Bayer Aktiengesellschaft Herbicidal disubstituted naphthalenes
EP2860169A3 (en) * 2009-04-17 2015-10-21 Centro De Neurociencias De Cuba Method for obtaining novel derivatives of naphtalene for the in vivo diagnosis of Alzheimer's disease

Also Published As

Publication number Publication date
NL8700358A (en) 1987-09-01
JPS62195344A (en) 1987-08-28
GR870258B (en) 1987-06-16
SE8700594L (en) 1987-08-16
ES2004879A6 (en) 1989-02-16
SE8700594D0 (en) 1987-02-13
DK75487A (en) 1987-08-16
SE465926B (en) 1991-11-18
DK75487D0 (en) 1987-02-13
GB8603778D0 (en) 1986-03-19

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