CH670084A5 - Prodn. of antiinflammatory 4-naphthyl-2-butanone deriv. - Google Patents
Prodn. of antiinflammatory 4-naphthyl-2-butanone deriv. Download PDFInfo
- 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
- Authority
- CH
- Switzerland
- Prior art keywords
- formula
- compound
- iii
- naphthyl
- reaction
- Prior art date
Links
- VEYCCHNUJNXSRR-UHFFFAOYSA-N 4-naphthalen-1-ylbutan-2-one Chemical compound C1=CC=C2C(CCC(=O)C)=CC=CC2=C1 VEYCCHNUJNXSRR-UHFFFAOYSA-N 0.000 title 1
- 230000003110 anti-inflammatory effect Effects 0.000 title 1
- BLXXJMDCKKHMKV-UHFFFAOYSA-N Nabumetone Chemical compound C1=C(CCC(C)=O)C=CC2=CC(OC)=CC=C21 BLXXJMDCKKHMKV-UHFFFAOYSA-N 0.000 claims abstract description 7
- 238000005903 acid hydrolysis reaction Methods 0.000 claims abstract description 6
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 4
- 150000001340 alkali metals Chemical class 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical group 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 229910052744 lithium Inorganic materials 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- UJOQSHCJYVRZKJ-UHFFFAOYSA-N 3-(1,3-benzoxazol-2-yl)-7-(diethylamino)chromen-2-one Chemical compound C1=CC=C2OC(C3=CC4=CC=C(C=C4OC3=O)N(CC)CC)=NC2=C1 UJOQSHCJYVRZKJ-UHFFFAOYSA-N 0.000 claims 1
- 102100024516 F-box only protein 5 Human genes 0.000 claims 1
- 101001052797 Homo sapiens F-box only protein 5 Proteins 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- -1 6-methoxy-2-naphthylmethyl halide Chemical class 0.000 abstract 1
- JIQXKYSNGXUDJU-UHFFFAOYSA-N propan-2-ylidenehydrazine Chemical compound CC(C)=NN JIQXKYSNGXUDJU-UHFFFAOYSA-N 0.000 abstract 1
- 150000007857 hydrazones Chemical class 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- RHUYHJGZWVXEHW-UHFFFAOYSA-N 1,1-Dimethyhydrazine Chemical compound CN(C)N RHUYHJGZWVXEHW-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229960004270 nabumetone Drugs 0.000 description 2
- JYLGKVDVIPITQM-UHFFFAOYSA-N 2-(chloromethyl)-6-methoxynaphthalene Chemical compound C1=C(CCl)C=CC2=CC(OC)=CC=C21 JYLGKVDVIPITQM-UHFFFAOYSA-N 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000002917 arthritic effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- 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)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB868603778A GB8603778D0 (en) | 1986-02-15 | 1986-02-15 | Chemical process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH670084A5 true CH670084A5 (en) | 1989-05-12 |
Family
ID=10593134
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH53687A CH670084A5 (en) | 1986-02-15 | 1987-02-13 | Prodn. of antiinflammatory 4-naphthyl-2-butanone deriv. |
Country Status (8)
| Country | Link |
|---|---|
| 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)
| 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)
| 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 |
-
1986
- 1986-02-15 GB GB868603778A patent/GB8603778D0/en active Pending
-
1987
- 1987-02-13 SE SE8700594A patent/SE465926B/en unknown
- 1987-02-13 GR GR870258A patent/GR870258B/en unknown
- 1987-02-13 NL NL8700358A patent/NL8700358A/en not_active Application Discontinuation
- 1987-02-13 DK DK75487A patent/DK75487A/en unknown
- 1987-02-13 ES ES8700375A patent/ES2004879A6/en not_active Expired
- 1987-02-13 CH CH53687A patent/CH670084A5/en not_active IP Right Cessation
- 1987-02-14 JP JP3229587A patent/JPS62195344A/en active Pending
Cited By (3)
| 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 |
|---|---|
| SE8700594L (en) | 1987-08-16 |
| SE465926B (en) | 1991-11-18 |
| NL8700358A (en) | 1987-09-01 |
| DK75487D0 (en) | 1987-02-13 |
| SE8700594D0 (en) | 1987-02-13 |
| ES2004879A6 (en) | 1989-02-16 |
| JPS62195344A (en) | 1987-08-28 |
| GB8603778D0 (en) | 1986-03-19 |
| DK75487A (en) | 1987-08-16 |
| GR870258B (en) | 1987-06-16 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |