DE214716C - - Google Patents
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- Publication number
- DE214716C DE214716C DENDAT214716D DE214716DA DE214716C DE 214716 C DE214716 C DE 214716C DE NDAT214716 D DENDAT214716 D DE NDAT214716D DE 214716D A DE214716D A DE 214716DA DE 214716 C DE214716 C DE 214716C
- Authority
- DE
- Germany
- Prior art keywords
- dimethyl
- pyrazolone
- alcohol
- oxymethyl
- parts
- Prior art date
- Legal status (The legal status 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 status listed.)
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- 229940100198 ALKYLATING AGENTS Drugs 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- NNZXDXMEXBYSRF-UHFFFAOYSA-N 2-methyl-4H-pyrazol-3-one Chemical compound CN1N=CCC1=O NNZXDXMEXBYSRF-UHFFFAOYSA-N 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000002844 melting Methods 0.000 description 5
- 239000003513 alkali Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- KPJPHPFMCOKUMW-UHFFFAOYSA-N iodomethane Chemical group I[CH2] KPJPHPFMCOKUMW-UHFFFAOYSA-N 0.000 description 3
- 230000011987 methylation Effects 0.000 description 3
- 238000007069 methylation reaction Methods 0.000 description 3
- 229960000583 Acetic Acid Drugs 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N Dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- CACWZFVIOGIBFP-UHFFFAOYSA-N 2,4,5-trimethyl-4H-pyrazol-3-one Chemical compound CC1C(C)=NN(C)C1=O CACWZFVIOGIBFP-UHFFFAOYSA-N 0.000 description 1
- KMVPXBDOWDXXEN-UHFFFAOYSA-N 4-nitrophenylhydrazine Chemical compound NNC1=CC=C([N+]([O-])=O)C=C1 KMVPXBDOWDXXEN-UHFFFAOYSA-N 0.000 description 1
- 229940040526 Anhydrous Sodium Acetate Drugs 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating Effects 0.000 description 1
- 230000001754 anti-pyretic Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 235000013312 flour Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N tin hydride Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/18—One oxygen or sulfur atom
- C07D231/20—One oxygen atom attached in position 3 or 5
- C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
- C07D231/26—1-Phenyl-3-methyl-5- pyrazolones, unsubstituted or substituted on the phenyl ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
KAISERLICHESIMPERIAL
Es wurde gefunden, daß man durch Einwirkung alkylierender Mittel auf das noch nicht beschriebene i-p-Aminophenyl-2 · 4-dimethyl-3-oxymethyl-5-pyrazolon Dialkylderivate, nämlich i-p-Dialkylaminophenyl-2 «4-dimethyl-3-oxymethyl-5-pyrazolone, darstellen kann, die sich durch eine hervorragend antipyretische Wirkung als therapeutisch wertvolle Verbindungen erwiesen haben. Die Überführung der primären Base in eine tertiäre kann beispielsweise durch Methylierung erfolgen, also etwa dadurch, daß man mit Methylalkohol und Jodmethyl oder ihren Ersatzmitteln erhitzt, oder indem man die bei zu weit gegangener Methylierung entstehende Ammoniumbase entmethyliert. It has been found that by the action of alkylating agents on the still i-p-aminophenyl-2 · 4-dimethyl-3-oxymethyl-5-pyrazolone dialkyl derivatives not described, namely i-p-Dialkylaminophenyl-2 «4-dimethyl-3-oxymethyl-5-pyrazolone, can represent, which through an excellent antipyretic effect as therapeutically valuable compounds have proven. The conversion of the primary base into a tertiary one can, for example take place by methylation, for example by using methyl alcohol and Iodomethyl or its substitutes heated, or by having gone too far The ammonium base formed by methylation is demethylated.
5 Teile i-p-Aminophenyl-2»4-dimethyl-3-oxymethyl-5-pyrazolon werden mit 3 Teilen Jodmethyl und 4 Teilen Methylalkohol 6 Stunden auf 90 bis ioo° erhitzt. Nach dem Abdestillieren des Alkohols wird der Rückstand in Wasser aufgenommen, mit Alkali übersättigt und die entstandene Dimethylaminobase mit Chloroform ausgeschüttelt. Der nach dem Abdestillieren des Chloroforms erhaltene Rückstand wird aus Wasser oder Alkohol umkristallisiert. 5 parts of i-p-aminophenyl-2 »4-dimethyl-3-oxymethyl-5-pyrazolone with 3 parts of iodomethyl and 4 parts of methyl alcohol for 6 hours heated to 90 to 100 °. After distilling off the alcohol, the residue becomes taken up in water, oversaturated with alkali and the resulting dimethylamino base extracted with chloroform. The one obtained after the chloroform has been distilled off The residue is recrystallized from water or alcohol.
233 Teile i-p-Aminophenyl-2 ■ 4-dimethyl-3-oxymethyl-5-pyrazolon werden unter Rühren allmählich mit 252 Teilen Dimethylsulfat vermischt, wobei die Reaktionstemperatur bis auf ioo° steigen darf. Ist sämtliches Dimethylsulfat eingetragen und hat die Selbsterwärmung aufgehört, so erwärmt man noch so lange auf 90 bis ioo°, bis die ganze primäre Base methyliert ist. Hierauf wird die Schmelze in Wasser gelöst, mit Natronlauge übersättigt und die methylierte Base mit Chloroform ausgezogen. Durch Umkristallisieren aus Wasser und Alkohol wird sie rein erhalten. 2 33 parts of ip-aminophenyl-2 4-dimethyl-3-oxymethyl-5-pyrazolone are gradually mixed with 252 parts of dimethyl sulfate with stirring, the reaction temperature being allowed to rise to 100 °. When all the dimethyl sulfate has been added and the self-heating has ceased, the temperature is continued to 90 to 100 ° until the entire primary base is methylated. The melt is then dissolved in water, supersaturated with sodium hydroxide solution and the methylated base is extracted with chloroform. It is obtained pure by recrystallization from water and alcohol.
Beispiel III.Example III.
Gleiche Teile i-p-Aminophenyl-2 · 4-dimethyl-3-oxymethylpyrazolon, Jodmethyl und Methylalkohol werden 10 bis 12 Stunden im geschlossenen Gefäß auf ioo° erhitzt. 10 Teile des so entstandenen Reaktionsproduktes, welches Ammoniumbase enthält, werden mit 3 Teilen entwässertem Natriumacetat und 20 Teilen Alkohol 10 bis 12 Stunden auf 140 bis 1500 erhitzt. Nach dem Erkalten wird der Alkohol abdestilliert, der Rückstand in Wasser aufgenommen, mit Natronlauge übersättigt und das i-p-Dimethylaminophenyl-2 · 4-dimethyl-3-oxymethylpyrazolon mit Chloroform ausgezogen. Durch Umkristallisieren aus Wasser und aus Alkohol wird die Verbindung gereinigt.Equal parts of ip-aminophenyl-2 · 4-dimethyl-3-oxymethylpyrazolone, iodomethyl and methyl alcohol are heated to 100 ° in a closed vessel for 10 to 12 hours. 10 parts of the resulting reaction product containing ammonium base are heated with 3 parts of anhydrous sodium acetate and 20 parts of alcohol 10 to 12 hours at 140 to 150 0th After cooling, the alcohol is distilled off, the residue is taken up in water, supersaturated with sodium hydroxide solution and the ip-dimethylaminophenyl-2 · 4-dimethyl-3-oxymethylpyrazolone is extracted with chloroform. The compound is purified by recrystallization from water and from alcohol.
Das i-p-Dimethylaminophenyl-2 · 4-dimethyl-3-oxymethyl-5-pyrazolon bildet ein farbloses Kristallmehl vom Schmelzpunkt 212 bis 2130. In Alkohol und Chloroform ist es leicht löslich, schwer löslich in kaltem Wasser, in Benzol und in Essigester. Mit Salzsäure bildet es einThe ip-dimethylaminophenyl-2 · 4-dimethyl-3-oxymethyl-5-pyrazolone forms a colorless crystal flour with a melting point of 212 to 213 0 . It is easily soluble in alcohol and chloroform, sparingly soluble in cold water, in benzene and in ethyl acetate. It forms a with hydrochloric acid
leichtlösliches, sauer reagierendes Dichlorhydrat. Easily soluble, acidic dichlorohydrate.
Das in den obigen Beispielen als Ausgangsstoff verwendete, noch nicht beschriebene i-p-Aminophenyl-2 · 4-dimethyl-3-oxymethyl-5-pyrazolon kann man aus i-p-Nitrophenyl-2 · 3 · 4-trimethyl-5-pyrazolon herstellen. Man erhält dieses, wenn man p-Nitrophenylhydrazin mit Methylacetessigester zu i-p-Nitrophenyl-3 · 4-dimethyl-5-pyrazolon kondensiert. Letzteres sowie auch das von Michaelis, Voß und Greiß (Ber. 34 [1901], S. 1302) dargestellte i-p-Nitrophenyl-3 · 4-dimethyl-5-chlorpyrazol liefern durch Methylieren das i-p-Nitrophenyl-2 · 3 · 4-trimethyl-5-pyrazolon . (p-Nitro-4-methylantipyrin), welches aus Benzol in gelben Blättchen vom Schmelzpunkt 1320 kristallisiert. Läßt man auf dieses nach dem Verfahren des Patents 206637 Brom und alsdann Alkali einwirken, so entsteht i-p-Nitrophenyl - 2 · 4 - dimethyl-3-brommethyl -5- pyrazolon, das aus Eisessig in gelben Kristallen erhalten wird, die bei 213 bis 2140 schmelzen. Kocht man die Lösung der 3-Brommethylverbindung in Eisessig mit Alkali acetat, so entsteht der Essigsäureester des i-p-Nitrophenyl-2 ·4-dimethylr3:oxymethyl-5-pyrazolons. Er bildet gelbe Kristalle vom Schmelzpunkt 163 bis 1640. Durch Kochen mit verdünnter Schwefelsäure ' wird das Acetat unter Bildung von i-p-Nitrophenyl-2 · 4-dimethyl-3-oxymethyl-5-pyrazolon verseift. Es bildet gelbe Kristalle vom Schmelzpunkt 178 bis 1790.The ip-aminophenyl-2 · 4-dimethyl-3-oxymethyl-5-pyrazolone used as starting material and not yet described can be prepared from ip-nitrophenyl-2 · 3 · 4-trimethyl-5-pyrazolone. This is obtained when p-nitrophenylhydrazine is condensed with methyl acetic acid ester to give ip-nitrophenyl-3 · 4-dimethyl-5-pyrazolone. The latter as well as the ip-nitrophenyl-3 · 4-dimethyl-5-chloropyrazole presented by Michaelis, Voss and Greiß (Ber. 34 [1901], p. 1302) give ip-nitrophenyl-2 · 3 · 4- by methylation. trimethyl-5-pyrazolone. (p-nitro-4-methylantipyrin), which crystallized from benzene in yellow flakes of melting point 132 0th If bromine and then alkali are allowed to act on this according to the method of patent 206637, ip-nitrophenyl-2 · 4-dimethyl-3-bromomethyl -5-pyrazolone is formed, which is obtained from glacial acetic acid in yellow crystals, which are obtained at 213 to 214 Melt 0. On boiling the solution of the 3-bromomethyl compound in glacial acetic acid with alkali acetate, the Essigsäureester formed of the ip-nitrophenyl-2 · 4-dimethyl r 3: oxymethyl-5-pyrazolone. It forms yellow crystals with a melting point of 163 to 164 0 . The acetate is saponified by boiling with dilute sulfuric acid to give ip-nitrophenyl-2 · 4-dimethyl-3-oxymethyl-5-pyrazolone. It forms yellow crystals with a melting point of 178 to 179 0 .
Reduziert man diesen Nitroalkohol oder sein; Acetat mittels Zinn und Salzsäure und übersättigt die eingedampfte entzinnte salzsaure Lösung mit Alkali, so fällt das i-p-Aminophenyl^^-dimethyl-s-oxymethyl-s-pyrazolon als Kristallmehl aus. Aus heißem Wasser kristallisiert die Base in farblosen Prismen vom Schmelzpunkt 2490. In den meisten organischen Lösungsmitteln ist diese Verbindung schwer löslich.If you reduce this nitro alcohol or be; Acetate using tin and hydrochloric acid and if the evaporated tinned hydrochloric acid solution is oversaturated with alkali, the ip-aminophenyl ^^ - dimethyl-s-oxymethyl-s-pyrazolone precipitates out as powdered crystals. The base crystallizes from hot water in colorless prisms with a melting point of 249 ° . This compound is sparingly soluble in most organic solvents.
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| Publication Number | Publication Date |
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| DE214716C true DE214716C (en) |
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