CH307809A - Process for the production of a new coumarin derivative. - Google Patents
Process for the production of a new coumarin derivative.Info
- Publication number
- CH307809A CH307809A CH307809DA CH307809A CH 307809 A CH307809 A CH 307809A CH 307809D A CH307809D A CH 307809DA CH 307809 A CH307809 A CH 307809A
- Authority
- CH
- Switzerland
- Prior art keywords
- production
- oxy
- parts
- chloro
- water
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 6
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- CFNMUZCFSDMZPQ-GHXNOFRVSA-N 7-[(z)-3-methyl-4-(4-methyl-5-oxo-2h-furan-2-yl)but-2-enoxy]chromen-2-one Chemical compound C=1C=C2C=CC(=O)OC2=CC=1OC/C=C(/C)CC1OC(=O)C(C)=C1 CFNMUZCFSDMZPQ-GHXNOFRVSA-N 0.000 title description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical group 0.000 claims description 6
- KZZRJVVATSFEQE-UHFFFAOYSA-M [I-].[Mg+]C1=CC=C(Cl)C=C1 Chemical compound [I-].[Mg+]C1=CC=C(Cl)C=C1 KZZRJVVATSFEQE-UHFFFAOYSA-M 0.000 claims description 4
- 239000007795 chemical reaction product Substances 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 2
- 150000002902 organometallic compounds Chemical class 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 alkyl radical Chemical group 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- GWQSENYKCGJTRI-UHFFFAOYSA-N 1-chloro-4-iodobenzene Chemical compound ClC1=CC=C(I)C=C1 GWQSENYKCGJTRI-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000000068 chlorophenyl group Chemical group 0.000 description 1
- 150000004775 coumarins Chemical class 0.000 description 1
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/42—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4
- C07D311/44—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3
- C07D311/46—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms in positions 2 and 4 with one hydrogen atom in position 3 unsubstituted in the carbocyclic ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Verfahren zur Herstellung eines neuen Cumarinderivates. Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von Cumarinderi- vaten der allgemeinen Formel
EMI0001.0005
worin R einen Alkylrest (vorzugsweise den Äthylrest) bedeutet.
Gemäss der vorliegenden Erfindung wer den diese Verbindungen dadurch erhalten, dass man auf ein 3-Acyl-4-oxy-cumarin der allgemeinen Formel
EMI0001.0009
worin R einen Alkylrest bedeutet, p-Chlor- phenyl-magnesiumjodid einwirken lässt, aus der entstandenen Verbindung Wasser abspal tet und das gebildete Reaktionsprodukt hy driert.
Als Ausgangsmaterial dient, ein 3-Aeyl- 4-oxy-eumarin. Es können beispielsweise 3 Acetyl-, 3-Propionyl-, 3-Butyroyl-4-oxy-euma- rin als Ausgangsmaterialien verwendet wer den, die nach einer bereits beschriebenen Me thode hergestellt werden. (J. Am. Chem. Soc. 72 [1950], Seite 5143; J. Chem. Soc. London, 1950, Seite 903; Annalen 347 [1906], Seite<B>1).</B>
Man lässt auf die Ausgangsverbindung p-Chlor-phenylmagnesiumjodid einwirken, wo bei zur Blockierung des aktiven Wasserstoff atoms der vierständigen Hydroxylgruppe ein Übersehuss des Chlorphenylderivates verwen det wird. Das hierbei entstehende tertiäre Carbinol der Formel
EMI0001.0027
braucht nicht isoliert zu werden, sondern kann sofort der Dehydratisierung unterwor fen werden.
Man bewerkstelligt diese Dehy- dratisierung vorzugsweise durch Erhitzen des Carbinols mit geringen Mengen p-Toluolsulfo- säure in Toluol, wobei das entstehende Was ser durch azeotrope Destillation mit dem To luol fortlaufend entfernt wird. Das für die Wasserabspaltung benötigte Wasserstoffatom wird von der ersten CH2-Gruppe des Alkyl- restes R des tertiären Carbinols geliefert.
Die ungesättigte Verbindung kann isoliert oder auch ohne Isolierung nach der Wasser abspaltung direkt der Hydrierung unterwor fen werden. Man. hydriert vorzugsweise in Dioxan oder Äthylalkohol in Gegenwart von Palladium-Kohle oder Raney-Nickel. Die .erfindungsgemäss hergestellten Ver bindungen stellen weisse, kristallisierte Sub stanzen dar.
Sie sind schwer löslich in Was ser und mässig löslich in den gebräuchlichen organisehen Lösungsmitteln. Pharmakologiseh zeichnen sie sich dadurch aus, dass sie den Prothrombinspiegel des Blutes in ganz gerin gen Konzentrationen zu senken vermögen.
Gegenstand des Patentes ist nun ein Ver fahren zur Herstellung von 3-(1'-p-Chlor- phenyl-propyl)-4-oxy-cumarin, das dadurch gekennzeichnet ist, dass man auf 3-Propionyl- 4-oxy-cumarin p-Chlor-phenyl-magnesium- jodid einwirken lässt, die erhaltene Organo- metallv erbindung hydrolytisch zersetzt, aus dem entstandenen Carbinol Wasser abspaltet und das gebildete Reaktionsprodukt hydriert.
Beispiel: In einer aus 3,8 Gewichtsteilen Magne sium und 36 Gewichtsteilen p-Chlor-jodben- zol in etwa. 400 Raumteilen absolutem Äther wie üblich zubereiteten p-Chlor-pheriylmagne- siumjodidlösung werden unter Rühren 10,3 Gewichtsteile 3-Propionyl-4-oxy-cumarin ein ; getragen und 3 Stunden lang unter Rüek- fluss gekocht. 1NTan zersetzt mit einem Gemisch von 15 Raumteilen konzentrierter Salzsäure und 400 Raumteilen Wasser.
Die Ätherschicht wird mit. 200 Raumteilen 3n-Natronlauge aus- a geschüttelt, die wässerigalkalische Schicht mit 50 Raumteilen Toluol gewaschen und hernach mit konzentrierter Salzsäure vorsichtig ange säuert. Das hierbei ausfallende Öl wird in 200 Raiunteilen Toluol aufgenommen, die Toluol- lösung mit 100 mg p-Toluolsulfosäure versetzt und am Wassersehender so lange am Rückfloss gekocht, bis sich keine Wassertröpfehen mehr abscheiden.
Hierauf wird die Toluollösung im Vakuum bei 40-50 C eingedampft und der Rückstand in 200 Raumteilen Alkohol gelöst,. wobei sich 0,3-0,4 Gewiehtsteile unveränder tes 3-Propionyl-4-oxy-cuniarin absehenden, die durch Filtration entfernt werden. Aus dem Filtrat wird der Alkohol im Vakuum ver dampft und das zurüekbleibende Harz mit . Äther angeteigt. Hierbei erfolgt die Abschei- dungvon 3-[a-(4'-Chlor-pbenyl)-prop-l-enyl]- 4-oxy-cumarin. Sehmelzpunkt 203-204 C.
3,7 Gewiehtsteile dieser Verbindung wer den in .50 Raumteilen Dioxan gelöst und un ter Zusatz von Raney-Niekel hydriert. Die für die Hydrierung der Doppelbindung be nötigte Wasserstoffmenge ist in etwa. 30-40 Minuten aufgenommen.
Nach Abfiltrieren des Katalysators, Abdampfen des Dioxans im Va kuum und Umkristallisieren aus Toluol er hält man das 3-(l.'-p-Chlor-phenyl-propyl)-4- oxy-cumarin in weissen Kristallen vom Schmelzpunkt 186-188 C.
Process for the production of a new coumarin derivative. The present invention relates to a process for the preparation of coumarin derivatives of the general formula
EMI0001.0005
where R is an alkyl radical (preferably the ethyl radical).
According to the present invention, these compounds are obtained by using a 3-acyl-4-oxy-coumarin of the general formula
EMI0001.0009
where R is an alkyl radical, p-chlorophenylmagnesium iodide can act, water is split off from the compound formed and the reaction product formed is hydrogenated.
The starting material is a 3-ayl-4-oxy-eumarin. For example, 3-acetyl, 3-propionyl, 3-butyroyl-4-oxy-eumarin can be used as starting materials, which are produced by a method already described. (J. Am. Chem. Soc. 72 [1950], page 5143; J. Chem. Soc. London, 1950, page 903; Annalen 347 [1906], page <B> 1). </B>
The starting compound p-chlorophenylmagnesium iodide is allowed to act, where an excess of the chlorophenyl derivative is used to block the active hydrogen atom of the tetravalent hydroxyl group. The resulting tertiary carbinol of the formula
EMI0001.0027
does not need to be isolated, but can be subjected to dehydration immediately.
This dehydration is preferably accomplished by heating the carbinol with small amounts of p-toluenesulfonic acid in toluene, the resulting water being continuously removed by azeotropic distillation with the toluene. The hydrogen atom required for dehydration is supplied by the first CH2 group of the alkyl radical R of the tertiary carbinol.
The unsaturated compound can be subjected to the hydrogenation directly after the water has been split off, either isolated or without isolation. Man. hydrogenated preferably in dioxane or ethyl alcohol in the presence of palladium-carbon or Raney nickel. The compounds produced in accordance with the invention are white, crystallized substances.
They are sparingly soluble in water and moderately soluble in common organic solvents. Pharmacologically, they are distinguished by the fact that they are able to lower the prothrombin level in the blood in very low concentrations.
The subject of the patent is now a process for the production of 3- (1'-p-chlorophenyl-propyl) -4-oxy-coumarin, which is characterized in that 3-propionyl-4-oxy-coumarin p -Chlor-phenyl-magnesium iodide to act, the resulting organometallic compound is hydrolytically decomposed, water is split off from the resulting carbinol and the reaction product formed is hydrogenated.
Example: In one made of 3.8 parts by weight of magnesium and 36 parts by weight of p-chloro-iodobenzene, roughly. 400 parts by volume of absolute ether, p-chloro-pheriylmagnesium iodide solution prepared as usual, are mixed in with 10.3 parts by weight of 3-propionyl-4-oxycoumarin; worn and cooked under reflux for 3 hours. 1NTan decomposes with a mixture of 15 parts by volume of concentrated hydrochloric acid and 400 parts by volume of water.
The ether layer is with. 200 parts by volume of 3N sodium hydroxide solution are shaken out, the aqueous-alkaline layer is washed with 50 parts by volume of toluene and then carefully acidified with concentrated hydrochloric acid. The oil which precipitates out is taken up in 200 raiunteile of toluene, 100 mg of p-toluenesulfonic acid are added to the toluene solution and refluxed on the water-seizing unit until no more water droplets separate.
The toluene solution is then evaporated in vacuo at 40-50 ° C. and the residue is dissolved in 200 parts by volume of alcohol. 0.3-0.4 parts by weight of unchanged 3-propionyl-4-oxy-cuniarin, which are removed by filtration. The alcohol is evaporated from the filtrate in vacuo and the resin that remains with it. Ether made into a paste. This results in the separation of 3- [a- (4'-chloro-pbenyl) -prop-1-enyl] -4-oxycoumarin. Sea melting point 203-204 C.
3.7 parts by weight of this compound are dissolved in .50 parts by volume of dioxane and hydrogenated under the addition of Raney-Niekel. The amount of hydrogen required for the hydrogenation of the double bond is approximately. Recorded for 30-40 minutes.
After filtering off the catalyst, evaporating the dioxane in vacuo and recrystallizing it from toluene, the 3- (l'- p-chloro-phenyl-propyl) -4-oxy-coumarin is obtained in white crystals with a melting point of 186-188 C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH307809T | 1952-08-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH307809A true CH307809A (en) | 1955-06-15 |
Family
ID=4493285
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH307809D CH307809A (en) | 1952-08-25 | 1952-08-25 | Process for the production of a new coumarin derivative. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH307809A (en) |
-
1952
- 1952-08-25 CH CH307809D patent/CH307809A/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE2244324A1 (en) | NEW 3-BENZOYLPROPIONIC ACID WITH TRIPLE SUBSTITUTED BENZYL RESIDUE AND PROCESS FOR THEIR PRODUCTION | |
| CH307809A (en) | Process for the production of a new coumarin derivative. | |
| DE1670118A1 (en) | Process for the preparation of new derivatives of 6,11-dihydro-dibenz [b, e] oxepins and their salts | |
| DE2160066A1 (en) | NEW BENZOPYRANE DERIVATIVES | |
| DE1936751A1 (en) | New heterocyclic compounds and their manufacturing process | |
| DE936091C (en) | Process for the preparation of 3- (p-oxy-substituted phenyl) -cyclohexanoic or -cyclohexencarboxylic acids and their esters | |
| DE764598C (en) | Process for the preparation of analgesic derivatives of 1-oxyphenyl-3-aminobutane | |
| DE810459C (en) | Process for the production of color photographic images | |
| CH307800A (en) | Process for the preparation of coumarin derivatives. | |
| DE1039063B (en) | Process for the preparation of an antipyretic, substituted 1, 2-diphenyl-3, 5-dioxo-pyrazolidine and its salts | |
| CH309833A (en) | Process for the production of a coumarin derivative. | |
| DE803235C (en) | Process for the preparation of 1-alkyl-3-benzhydrylpiperidines | |
| CH309832A (en) | Process for the production of a coumarin derivative. | |
| DE1470063C3 (en) | 5- (alpha-Hy droxy-alpha-pheny 1-alpha square bracket to 2-pyridyl square bracket to -methyl) -7 ^ phenyl-2-pyridylmethylene) -5-norbornene-2,3-dicarboximide, their acid addition salts and method to their manufacture | |
| DE414598C (en) | Process for the production of dihydrodeoxymorphine and dihydrodeoxycodeine | |
| AT233552B (en) | Process for the preparation of new dibenzocycloheptadiene derivatives and their salts | |
| DE699309C (en) | Process for the preparation of pregnenolones | |
| CH309834A (en) | Process for the production of a coumarin derivative. | |
| DE2543732A1 (en) | DERIVATIVES OF 3ALPHA,5ALPHA-CYCLO-6BETA-ALKOXY-25-HYDROXYCHOLESTEROL AND 3ALPHA,5ALPHA-CYCLO-6BETA-ALKOXYCHOLEST-22T-EN-24,25-OXIDE, METHOD FOR PRODUCING THE SAME AND INTERMEDIATE PRODUCTS FOR HYDROXYLATED VITA MIN D LOW 2 AND D DEEP 3 | |
| CH309835A (en) | Process for the production of a coumarin derivative. | |
| DE1470262C3 (en) | 4H-Benzo 4,5 cyclohepta 1,2-b thiophenes | |
| DE623373C (en) | ||
| AT238888B (en) | Process for the preparation of new 3α-hydroxy-11,20-dioxo-21-pregnanglyoxylic acids substituted in the 16-position by a methyl group | |
| CH309836A (en) | Process for the production of a coumarin derivative. | |
| DE820310B (en) | Process for the production of thiophane derivatives |