CH617191A5 - Process for the preparation of novel benzylpyrimidines - Google Patents
Process for the preparation of novel benzylpyrimidines Download PDFInfo
- Publication number
- CH617191A5 CH617191A5 CH1499977A CH1499977A CH617191A5 CH 617191 A5 CH617191 A5 CH 617191A5 CH 1499977 A CH1499977 A CH 1499977A CH 1499977 A CH1499977 A CH 1499977A CH 617191 A5 CH617191 A5 CH 617191A5
- Authority
- CH
- Switzerland
- Prior art keywords
- acid
- methyl
- ethyl acetate
- amino
- dimethylamino
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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
- C07D211/56—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
- C07D239/49—Two nitrogen atoms with an aralkyl radical, or substituted aralkyl radical, attached in position 5, e.g. trimethoprim
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Cosmetics (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Die Erfindung betrifft ein Verfahren zur Herstellung neuer Benzylpyrimidine der allgemeinen Formel worin The invention relates to a process for the preparation of new benzylpyrimidines of the general formula wherein
R1 Amino oder -NHR3; R2 Amino, Pyrrolo, Pyrrolidino, Piperidino, -NHR3 oder -N(R3)2; R3 C^-Alkyl oder C2_4-Alkenyl und Z Wasserstoff, Chlor, Brom, Pyrrolo, Pyrrolidino, Piperidino, Morpholino, R3, OR3 oder -N(R3)2 darstel- 20 len, R1 amino or -NHR3; R2 amino, pyrrolo, pyrrolidino, piperidino, -NHR3 or -N (R3) 2; R3 represents C ^ alkyl or C2_4 alkenyl and Z represents hydrogen, chlorine, bromine, pyrrolo, pyrrolidino, piperidino, morpholino, R3, OR3 or -N (R3) 2,
und von deren Salzen, dadurch gekennzeichnet, dass man eine Verbindung and of their salts, characterized in that one has a compound
25 25th
r1 r1
•p- • p-
R R
CH2 CH2
nh2 nh2
r1 r1
R2 R2
r—-N r —- N
ch2 —\ nh2 h2n worin ch2 - \ nh2 h2n where
R1 Amino oder -NHR3; R2 Amino, Pyrrolo, Pyrrolidino, IIa Piperidino, NHR3 oder -N(R3)2; R3 C^-AIkyl oder C2_4-Al-30 kenyl und Z Wasserstoff, Chlor, Brom, Pyrrolo, Pyrrolidino, Piperidino, Morpholino, R3, OR3 oder -N(R3)2 darstellen, und von deren Salzen. R1 amino or -NHR3; R2 amino, pyrrolo, pyrrolidino, IIa piperidino, NHR3 or -N (R3) 2; R3 is C ^ alkyl or C2_4-Al-30 kenyl and Z is hydrogen, chlorine, bromine, pyrrolo, pyrrolidino, piperidino, morpholino, R3, OR3 or -N (R3) 2, and of their salts.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man eine Verbindung The method according to the invention is characterized in that a connection
35 35
40 40
IIb nh2 IIb nh2
IIa IIa
45 45
oder or
H H
ch2 ch2
-ö- -ö-
£ £
r r
10 10th
50 50
Ile Ile
55 55
oder or
IIb worin IIb where
R4 ein zu einer Amino- oder R3NH-Gruppe hydrolysierbarer Rest; R5 Amino, Pyrrolo, Pyrrolidino, Piperidino, -NHRJ, -N(R3)2 oder ein zu einer Amino- oder R3NH-Grup-pe hydrolysierbarer Rest und R6 und R10 ein zu einer Amino-gruppe hydrolysierbarer Rest ist und R1, R2 sowie Z die oben angegebenen Bedeutungen haben, R4 is a radical which can be hydrolyzed to an amino or R3NH group; R5 is amino, pyrrolo, pyrrolidino, piperidino, -NHRJ, -N (R3) 2 or a radical which can be hydrolyzed to an amino or R3NH group and R6 and R10 is a radical which can be hydrolyzed to an amino group and R1, R2 and Z have the meanings given above,
hydrolysiert und die erhaltene Verbindung gewünschtenfalls in ein Salz überführt. hydrolyzed and the compound obtained, if desired, converted into a salt.
60 60
65 65
R R
ch ch
<' <'
y«" y «"
Ile Ile
3 3rd
617191 617191
worin wherein
R4 ein zu einer Amino- oder R3NH-Gruppe hydrolysierbarer Rest; R1*' Amino, Pyrrolo, Pyrrolidino, Piperidino, -NHR3, -N(R3)2 oder ein zu einer Amino- oder R3NH-Grup-pe hydrolysierbarer Rest und R° ein zu einer Aminogruppe hydrolysierbarer Rest ist und R1, R2 sowie Z die oben angegebenen Bedeutungen haben, R4 is a radical which can be hydrolyzed to an amino or R3NH group; R1 * 'amino, pyrrolo, pyrrolidino, piperidino, -NHR3, -N (R3) 2 or a radical which can be hydrolyzed to an amino or R3NH group and R ° is a radical which can be hydrolyzed to an amino group and R1, R2 and Z have the meanings given above,
hydrolysiert und die erhaltene Verbindung gewünschtenfalls in ein Salz überführt. hydrolyzed and the compound obtained, if desired, converted into a salt.
Die hier verwendeten Ausdrücke «C1_4» und «C2_4» bezeichnen Gruppen mit 1-4 bzw. 2-4 Kohlenstoffatomen. AI-kyl-, Alkoxy-, Alkenyl- und Alkenyloxygruppen können geradkettig oder verzweigt sein und enthalten zweckmässig eine niedere C-Anzahl. Beispiele solcher Gruppen sind Methyl, Äthyl, Propyl, Isopropyl, tert.-Butyl, Methoxy, Äthoxy, Propoxy und Isopropoxy; Vinyl, Allyl, Vinyloxy und Allyl-oxy. The terms “C1_4” and “C2_4” used here refer to groups with 1-4 and 2-4 carbon atoms. Al-kyl, alkoxy, alkenyl and alkenyloxy groups can be straight-chain or branched and suitably contain a lower C number. Examples of such groups are methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy and isopropoxy; Vinyl, allyl, vinyloxy and allyloxy.
Beispiele von hydrolytisch in eine Amino- oder R3-NH--Gruppe überführbaren Resten R4, R5 und R6 sind -NHR7, -N=CHR, -N=C(R)2, -N=CHOR:i, -NHCOOR3, -NR3-COOR3, -NR3R7 und Phthalimido, wobei R Alkyl, Alkenyl oder Aryl darstellt, R8 die oben angegebene Bedeutung hat und R7 der Acylrest einer vorzugsweise niederen aliphatischen Carbonsäure oder einer Sulfonsäure darstellt. Besonders geeignete hydrolysierbare Gruppen R° sind Formylamino, Acet-amino, Phthalimido oder Carbobenzoxyamino. Examples of radicals R4, R5 and R6 which can be converted hydrolytically into an amino or R3-NH group are -NHR7, -N = CHR, -N = C (R) 2, -N = CHOR: i, -NHCOOR3, - NR3-COOR3, -NR3R7 and phthalimido, where R represents alkyl, alkenyl or aryl, R8 has the meaning given above and R7 represents the acyl radical of a preferably lower aliphatic carboxylic acid or a sulfonic acid. Particularly suitable hydrolyzable groups R ° are formylamino, acetamino, phthalimido or carbobenzoxyamino.
Die Hydrolyse dieser Gruppen wird zweckmässig in saurem Medium, z.B. mit wässrigen oder wässrig-alkoholischen Mineralsäuren, wie Salzsäure, durchgeführt. Alkalisch hydrolysierbare Gruppen sind die Gruppen -NR3COOR3, -NH-COOR3 und -NHCHO. Die alkalische Hydrolyse kann mit wässrigem oder wässrig-alkoholischem (methanolischem) Alkali erfolgen. Die Phthalimidogruppe kann, vorzugsweise, durch Hydrazinolyse in die Aminogruppe umgewandelt werden. The hydrolysis of these groups is conveniently carried out in an acidic medium, e.g. with aqueous or aqueous-alcoholic mineral acids, such as hydrochloric acid. Alkaline hydrolyzable groups are the groups -NR3COOR3, -NH-COOR3 and -NHCHO. The alkaline hydrolysis can be carried out with aqueous or aqueous-alcoholic (methanolic) alkali. The phthalimido group can, preferably, be converted to the amino group by hydrazinolysis.
Für die Herstellung von Säureadditionssalzen, insbesondere von in pharmazeutischen Präparaten brauchbaren Salzen, kommen die üblicherweise für diesen Zweck verwendeten anorganischen Säuren, wie Salzsäure, Schwefelsäure, Phosphorsäure, etc. oder organischen Säuren, wie Ameisensäure, Essigsäure, Bernsteinsäure, Milchsäure, Citronensäure, Maleinsäure, Fumarsäure, Weinsäure, Methansulfonsäure, p-Toluolsulfonsäure etc. in Betracht. For the production of acid addition salts, in particular salts which can be used in pharmaceutical preparations, the inorganic acids usually used for this purpose, such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., or organic acids, such as formic acid, acetic acid, succinic acid, lactic acid, citric acid, maleic acid, Fumaric acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid etc. into consideration.
Die Verbindungen der Formel I und ihre Salze sind antibakteriell wirksam. Sie hemmen die bakterielle Dihydro-folat-Reduktase und potenzieren die antibakterielle Wirkung von Sulfonamiden, wie z.B. Sulfisoxazol, Sulfadimethoxin, Sulfamethoxazol, 4-Sulfanilamido-5,6-dimethoxy-pyrimidin, 2-SulfaniIamido-4,5-dimethyl-pyrimidin oder Sulfachinoxalin, Sulfadiazin, Sulfamonomethoxin, 2-SulfaniIamido-4,5-dime-thyl-isoxazol und anderen Inhibitoren für Enzyme, die an der Folsäurebiosynthese beteiligt sind, wie z.B. Pteridinderi-vate. The compounds of formula I and their salts are antibacterial. They inhibit the bacterial dihydro-folate reductase and potentiate the antibacterial effect of sulfonamides, e.g. Sulfisoxazole, sulfadimethoxin, sulfamethoxazole, 4-sulfanilamido-5,6-dimethoxy-pyrimidine, 2-sulfaniIamido-4,5-dimethyl-pyrimidine or sulfachinoxaline, sulfadiazine, sulfamonomethoxine, 2-sulfaniIamido-4,5-dimethyl-isoxazole and other inhibitors for enzymes involved in folic acid biosynthesis, such as Pteridinderi-vate.
Für solche Kombinationen einer oder mehrerer der er-findungsgemässen Verbindungen I mit Sulfonamiden kommt in der Humanmedizin orale, rectale und parenterale Applikation in Frage. Das Verhältnis von Verbindung I zu Sulfonamid kann innerhalb eines weiten Bereiches variieren; es beträgt z.B. zwischen 1:40 (Gewichtsteile) und.5:1 (Gewichtsteil); bevorzugte Verhältnise sind 1:1 bis 1:5. For such combinations of one or more of the compounds I according to the invention with sulfonamides, oral, rectal and parenteral administration are suitable in human medicine. The ratio of compound I to sulfonamide can vary within a wide range; it is e.g. between 1:40 (parts by weight) and 5: 1 (parts by weight); preferred ratios are 1: 1 to 1: 5.
So kann z.B. eine Tablette 80 mg einer erfindungsgemäs-sen Verbindung I und 400 mg Sulfamethoxazol, eine Kindertablette 20 mg einer erfindungsgemässen Verbindung I und 100 mg Sulfamethoxazol; Sirup (pro 5 ml) 40 mg Verbindung 1 und 200 mg Sulfamethoxazol enthalten. For example, one tablet 80 mg of a compound I according to the invention and 400 mg of sulfamethoxazole, one child's tablet 20 mg of a compound I according to the invention and 100 mg of sulfamethoxazole; Syrup (per 5 ml) contain 40 mg of compound 1 and 200 mg of sulfamethoxazole.
Die Verbindungen der Formel I zeichnen sich durch eine hohe antibakterielle Wirksamkeit bzw. einen ausgeprägten synergistischen Effekt in Kombination mit Sulfonamiden und gute Verträglichkeit aus. The compounds of the formula I are notable for high antibacterial activity or a pronounced synergistic effect in combination with sulfonamides and good tolerance.
Die nachstehenden Beispiele erläutern die Erfindung. Die Temperaturen sind in Celsiusgraden angegeben. The following examples illustrate the invention. The temperatures are given in degrees Celsius.
Beispiel 1 example 1
4,0 g 5'-<(2,4-Diamino-5-pyrimidinyl)-methyl>-3'-(dime-thylamino)-2'-methoxy-N-methylacetanilid und 4.0 g of 5 '- <(2,4-diamino-5-pyrimidinyl) methyl> -3' - (dimethylamino) -2'-methoxy-N-methylacetanilide and
100 ml IN Salzsäure wurden 2 Stunden unter Rückfluss gekocht. 100 ml IN hydrochloric acid were refluxed for 2 hours.
Nach Neutralisation und Eindampfen im Vakuum, Reinigen des Rückstandes über Silikagel mit Methylenchlorid-Propanol (8:2) und Umkristallisieren aus Äthanol wurde das 2,4-Diamino-5-<3-(dimethylamino)-4-methoxy-5-(methylami-no)benzyl>pyrimidin vom Smp. 183° erhalten. After neutralization and evaporation in vacuo, cleaning of the residue over silica gel with methylene chloride-propanol (8: 2) and recrystallization from ethanol, the 2,4-diamino-5- <3- (dimethylamino) -4-methoxy-5- (methylami -no) benzyl> pyrimidine of mp. 183 ° obtained.
Das Ausgangsmaterial wurde wie folgt hergestellt: The starting material was produced as follows:
Ein Gemisch von 29,4 g 3,5-Diamino-4-methoxybenzoe-säuremethylester, 57,3 ml Dimethylsulfat, 207 g trockenem Kaliumcarbonat und 1000 ml Aceton wurde 16 Stunden unter Rühren und unter Rückfluss gekocht. Nach dem Erkalten wurde die Lösung von anorganischen Salzen filtriert, das Aceton im Vakuum entfernt, der Rückstand mit 200 ml Wasser versetzt, das ausgefallene Öl zweimal mit je 300 ml Essigester extrahiert, die Essigesterlösung mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft. Es hinterblieb ein Öl, aus dem durch Säulenchromatographie über Silikagel mit Methylenchlorid-Essigester (9:1) 3-(Dime-thylamino)-5-(methylamino)-p-anissäuremethylester und 3,5--Bis(dimethylamino)-p-anissäuremethylester isoliert wurden. A mixture of 29.4 g of 3,5-diamino-4-methoxybenzoic acid methyl ester, 57.3 ml of dimethyl sulfate, 207 g of dry potassium carbonate and 1000 ml of acetone was boiled for 16 hours with stirring and under reflux. After cooling, the solution of inorganic salts was filtered, the acetone was removed in vacuo, the residue was mixed with 200 ml of water, the precipitated oil was extracted twice with 300 ml of ethyl acetate each time, the ethyl acetate solution was washed with water, dried over sodium sulfate and evaporated. An oil remained, from which by column chromatography over silica gel with methylene chloride-ethyl acetate (9: 1) 3- (dimethylamino) -5- (methylamino) -p-anisic acid methyl ester and 3,5 - bis (dimethylamino) -p- methyl anisate were isolated.
25 g 3-(Dimethylamino)-5-(methylamino)-p-anissäureme-thylester und 100 ml Essigsäureanhydrid wurde eine Stunde auf dem Dampfbad erwärmt. Der Überschuss an Anhydrid wurde im Vakuum entfernt und der Rückstand aus hochsiedendem Petroläther umkristallisiert. Der 3-(Dimethylami-no)-5-(N-methylacetamido)-p-anissäuremethylester schmolz bei 88-89°. 25 g of methyl 3- (dimethylamino) -5- (methylamino) -p-anisate and 100 ml of acetic anhydride were heated on the steam bath for one hour. The excess anhydride was removed in vacuo and the residue was recrystallized from high-boiling petroleum ether. The methyl 3- (dimethylamino) -5- (N-methylacetamido) -p-anisate melted at 88-89 °.
Eine Suspension von 7,05 g Dimethylsulfon und 2,4 g Natriumhydrid (50% ige Dispersion in Öl) in 18 ml Dime-thylsulfoxid wurde unter Feuchtigkeitsausschluss 2 Stunden bei 50° gerührt. Darauf wurden 6,95 g 3-(Dimethylamino)-5--(N-methylacetamido)-p-anissäuremethylester hinzugegeben und die Mischung eine Stunde bei Raumtemperatur gerührt. Die Lösung wurde mit 100 ml Wasser verdünnt, mit Essigsäure sauer gestellt und zweimal mit Essigester extrahiert. Die Essigesterphasen wurden vereinigt, mit Wasser gewaschen, über Natriumsulfat getrocknet und im Vakuum zur Trockene eingedampft. Nach Umkristallisieren des Rückstandes aus Methanol schmolz das 3'-(Dimethylamino)-2'-meth-oxy-N-methy 1-5'- < (methy lsu I fonyl) acetyUacetanilid bei 174-176°. A suspension of 7.05 g of dimethyl sulfone and 2.4 g of sodium hydride (50% dispersion in oil) in 18 ml of dimethyl sulfoxide was stirred at 50 ° for 2 hours with exclusion of moisture. Then 6.95 g of methyl 3- (dimethylamino) -5 - (N-methylacetamido) -p-anisate were added and the mixture was stirred for one hour at room temperature. The solution was diluted with 100 ml of water, acidified with acetic acid and extracted twice with ethyl acetate. The ethyl acetate phases were combined, washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. After the residue had been recrystallized from methanol, the 3 '- (dimethylamino) -2'-meth-oxy-N-methyl 1-5'- <(methyl lsu I fonyl) acetyuacetanilide melted at 174-176 °.
Eine Suspension von 10.9 g 3'-(Dimethylamino)-2'-meth-oxy-N-methyl-5'-<(methylsulfonyl)acetyl>acetanilid und 0,40 g Natriumborhydrid in 50 ml 85%igem wässerigem Äthanol wurde anderthalb Stunden bei 20° gerührt, mit Essigsäure neutral gestellt und in Vakuum eingeengt. Das ausgefallene Öl wurde mit Essigester extrahiert, die Essigesterlösung eingedampft und der Rückstand aus Essigester-Petroläther umkristallisiert. Das 3'-(Dimethylamino)-5'-<l-hydroxy-2-(me-thylsulfonyl)äthyl>-2'-methoxy-N-methvlacetanilid schmolz bei 118-119°. A suspension of 10.9 g of 3 '- (dimethylamino) -2'-meth-oxy-N-methyl-5' - <(methylsulfonyl) acetyl> acetanilide and 0.40 g of sodium borohydride in 50 ml of 85% aqueous ethanol was used for one and a half hours stirred at 20 °, neutralized with acetic acid and concentrated in vacuo. The precipitated oil was extracted with ethyl acetate, the ethyl acetate solution was evaporated and the residue was recrystallized from ethyl acetate-petroleum ether. The 3 '- (dimethylamino) -5' - <l-hydroxy-2- (methylsulfonyl) ethyl> -2'-methoxy-N-methvlacetanilide melted at 118-119 °.
Eine Mischung von 10,6 g 3'-(Dimethylamino)-5'-<l-hy-droxy-2-(methylsulfonyl)äthyl>-2,-methoxy-N-methylacetani-lid, 1,8 g Natriummethylat und 4,8 g ß-Anilinopropionitril in 20 ml Dimethylsulfoxid wurde unter Feuchtigkeitsausschluss 5 Stunden bei 50° gerührt. Die Mischung wurde in 250 ml Wasser gegossen, das ausgefallene Öl mit Essigester extrahiert, die Essigesterlösung über Natriumsulfat getrocknet und eingedampft. Durch Reinigen des Rückstandes über A mixture of 10.6 g of 3 '- (dimethylamino) -5' - <l-hydroxy-2- (methylsulfonyl) ethyl> -2, -methoxy-N-methylacetanidide, 1.8 g of sodium methylate and 4 , 8 g of β-anilinopropionitrile in 20 ml of dimethyl sulfoxide was stirred for 5 hours at 50 ° with exclusion of moisture. The mixture was poured into 250 ml of water, the precipitated oil was extracted with ethyl acetate, the ethyl acetate solution was dried over sodium sulfate and evaporated. By cleaning the residue over
5 5
10 10th
15 15
20 20th
25 25th
30 30th
35 35
40 40
45 45
50 50
55 55
60 60
65 65
617191 617191
4 4th
Aluminiumoxid mit Benzol und Umkristallisieren aus Essig-ester-Petroläther wurde das 5'-(3-Anilino-2-cyanoallyl)-3'-(di-methylamino)-2'-methoxy-N-methylacetaniIid vom Smp. 176-178° erhalten. Aluminum oxide with benzene and recrystallization from ethyl acetate-petroleum ether became the 5 '- (3-anilino-2-cyanoallyl) -3' - (dimethylamino) -2'-methoxy-N-methylacetaniIid of mp. 176-178 ° receive.
Eine Lösung von 1,7 g Natrium in 110 ml absolutem Äthanol wurde mit 7,04 g Guanidjn-hydrochlorid und 9,2 g 5,-(3-Anilino-2-cyanoallyl)-3,-(dimethylamino)-2'-methoxy--N-methylacetanilid versetzt und 20 Stunden unter Rückfluss gekocht. Der Alkohol wurde im Vakuum entfernt, der Rückstand in Wasser aufgenommen, der Feststoff abgesaugt und aus Äthanol umkristallisiert. Das 5'-<(2,4-Diamino-5-pyrimi-dinyl)methyl>-3'-(dimethylamino)-2'-methoxy-N-methylacet-anilid schmolz bei 220-222°. A solution of 1.7 g sodium in 110 ml absolute ethanol was mixed with 7.04 g guanidine hydrochloride and 9.2 g 5, - (3-anilino-2-cyanoallyl) -3, - (dimethylamino) -2'- methoxy - N-methylacetanilide added and boiled under reflux for 20 hours. The alcohol was removed in vacuo, the residue was taken up in water, the solid was filtered off with suction and recrystallized from ethanol. The 5 '- <(2,4-diamino-5-pyrimidinyl) methyl> -3' - (dimethylamino) -2'-methoxy-N-methylacetanilide melted at 220-222 °.
Beispiel 2 Example 2
2,0 g N-<alphar,-(2,4-Diamino-5-pyrimidinyl)-3-(pyrrol-l--yl)-2,5-xylyl>acetamid und 70 ml IN Salzsäure wurden 3 Stunden auf dem Dampfbad erwärmt. Nach dem Erkalten wurde die Lösung mit Kaliumcarbonat alkalisch gemacht, der Niederschlag abgenutscht und aus Ätha-nol-Petroläther umkristallisiert. Das 2,4-Diamino-5-<3-ami-no-4-methyl-5-(pyrrol-l-yl)benzyl>pyrimidin schmolz bei 202-204°. 2.0 g of N- <alphar, - (2,4-diamino-5-pyrimidinyl) -3- (pyrrol-l - yl) -2,5-xylyl> acetamide and 70 ml of 1N hydrochloric acid were placed on the Steam bath warmed. After cooling, the solution was made alkaline with potassium carbonate, the precipitate was filtered off and recrystallized from ethanol-petroleum ether. The 2,4-diamino-5- <3-amino-4-methyl-5- (pyrrol-l-yl) benzyl> pyrimidine melted at 202-204 °.
Das Ausgangsmaterial wurde wie folgt hergestellt: The starting material was produced as follows:
Eine Mischung von 18 g 3,5-Diamino-4-methylbenzoe-säuremethylester, 0,7 g p-Toluolsulfonsäure, 8,2 g Natrium-acetat, 32 g Diäthoxytetrahydrofuran, 10 ml Eisessig, 100 ml Äthanol und 100 ml Wasser wurden 3 Stunden am Rückfluss gekocht. Der Alkohol wurde im Vakuum entfernt und, der Rückstand mit Essigester extrahiert. Die Essigesterlösung wurde mit Wasser gewaschen, über Natriumsulfat getrocknet und eingedampft. Durch Reinigen des Rückstandes über Aluminiumoxid mit Essigester und Umkristallisieren aus hochsiedendem Petroläther wurde der 3-Amino-4-methyl-5-(pyrrol-l--yl)benzoesäuremethylester vom Smp. 112° erhalten. A mixture of 18 g of 3,5-diamino-4-methylbenzoic acid methyl ester, 0.7 g of p-toluenesulfonic acid, 8.2 g of sodium acetate, 32 g of diethoxytetrahydrofuran, 10 ml of glacial acetic acid, 100 ml of ethanol and 100 ml of water was 3 Cooked at reflux for hours. The alcohol was removed in vacuo and the residue extracted with ethyl acetate. The ethyl acetate solution was washed with water, dried over sodium sulfate and evaporated. The 3-amino-4-methyl-5- (pyrrol-l - yl) benzoic acid methyl ester of mp 112 ° was obtained by purifying the residue over aluminum oxide with ethyl acetate and recrystallizing from high-boiling petroleum ether.
Eine Suspension von 4,6 g 3-Amino-4-methyl-5-(pyrrol-l--yl)-benzoesäuremethylester in 15 ml Eisessig wurde mit 2,1 g Acetanhydrid versetzt. Unter Selbsterwärmung entstand zuerst eine klare Lösung und bald darauf begannen sich Kristalle abzuscheiden. Es wurde noch 30 Minuten auf dem Dampfbad erwärmt und darauf abgekühlt. Die Kristalle wurden abgesaugt und aus Methanol umkristallisiert. Der 3-Acet- A suspension of 4.6 g of methyl 3-amino-4-methyl-5- (pyrrol-1-yl) benzoate in 15 ml of glacial acetic acid was mixed with 2.1 g of acetic anhydride. Under self-heating, a clear solution first emerged and soon after, crystals began to separate out. The mixture was heated on the steam bath for a further 30 minutes and then cooled. The crystals were filtered off and recrystallized from methanol. The 3-acet
amido-4-methyl-5-(pyrrol-l-yl)benzoesäuremethylester schmolz bei 184-185°. amido-4-methyl-5- (pyrrol-l-yl) methyl benzoate melted at 184-185 °.
Eine Suspension von 1,44 g Natriumhydrid (50%ige Dispersion in Öl) und 3,7 g Dimethylsulfon in 20 ml Dime-5 thylsulfoxid wurde unter Feuchtigkeitsausschluss 2 Stunden bei 50° gerührt. Darauf wurden 5,45 g 3-Acetamido-4-methyl--5-(pyrrol-l-yl)benzoesäuremethylester hinzugegeben und die Mischung 2 Stunden bei Zimmertemperatur gerührt. Die Lösung wurde mit 200 ml Wasser verdünnt, die wässerige io Lösung mit Essigester gewaschen, mit Essigsäure leicht sauer gestellt und über Nacht im Kühlschrank stehengelassen. Am folgenden Tag wurde der Niederschlag abgesaugt und aus Äthanol umkristallisiert. Das 5'-<(MethylsulfonyI)acetyl>-3'--(pyrrol-l-yl)-o-acetotoluidid schmolz bei 212-214°. 15 Eine Suspension von 1,6 g 5'-<(Methylsulfonyl)acetyl>--3'-(pyyrol-l-yl)-o-acetotoluidid und 0,40 g Natriumborhydrid in 50 ml 50%igem wässerigem Äthanol wurde 30 Minuten bei Zimmertemperatur gerührt. Der Äthanol wurde im Vakuum entfernt, der Niederschlag abgesaugt, getrocknet und 20 aus Essigester-Petroläther umkristallisiert. Das 5'-<l-Hy-droxy-(2-methylsulfonyl)äthyl>-3'-(pyrrol-l-yl)-o-acetotoluidid schmolz bei 167-168°. A suspension of 1.44 g of sodium hydride (50% dispersion in oil) and 3.7 g of dimethyl sulfone in 20 ml of dime-5-ethyl sulfoxide was stirred at 50 ° for 2 hours with exclusion of moisture. 5.45 g of methyl 3-acetamido-4-methyl-5- (pyrrol-l-yl) benzoate were then added and the mixture was stirred at room temperature for 2 hours. The solution was diluted with 200 ml of water, the aqueous solution was washed with ethyl acetate, made slightly acidic with acetic acid and left in the refrigerator overnight. The following day, the precipitate was filtered off and recrystallized from ethanol. The 5 '- <(methylsulfonyI) acetyl> -3' - (pyrrol-l-yl) -o-acetotoluidide melted at 212-214 °. 15 A suspension of 1.6 g of 5 '- <(methylsulfonyl) acetyl> - 3' - (pyyrol-l-yl) -o-acetotoluidide and 0.40 g of sodium borohydride in 50 ml of 50% aqueous ethanol was 30 minutes stirred at room temperature. The ethanol was removed in vacuo, the precipitate was filtered off, dried and recrystallized from ethyl acetate-petroleum ether. The 5 '- <l-hydroxy- (2-methylsulfonyl) ethyl> -3' - (pyrrol-l-yl) -o-acetotoluidide melted at 167-168 °.
Eine Mischung von 1,35 g5'-(l-Hydroxy-2-(methylsulfo-nyl)-äthyl-3'-(pyrrol-l-yl)-o-acetotoluidid, 0,43 gNatrium-25 methylat und 1,1g ß-Anilinopropionitril in 12 ml Dimethyl-sulfoxid wurde unter Feuchtigkeitsausschluss 1 Std. bei Zimmertemperatur gerührt. Die Mischung wurde in 100 ml Wasser gegossen, das ausgefallene Öl mit Essigester extrahiert, die Essigesterlösung mit Wasser gewaschen, über Natrium-30 sulfat getrocknet und eingedampft. Durch Säulenchromatographie über Silikagel mit Methylenchlorid-Essigester (9:1) und Umkristallisieren aus Äthanol wurde das 5'-(3-Anilino--2-cyanoallyl)-3'-(pyrrol-l-yl)-o-acetotoluidid vom Smp. 218-220° erhalten. A mixture of 1.35 g of 5 '- (l-hydroxy-2- (methylsulfonyl) ethyl) 3' - (pyrrol-l-yl) -o-acetotoluidide, 0.43 g of sodium 25 methylate and 1.1 g β-anilinopropionitrile in 12 ml of dimethyl sulfoxide was stirred for 1 hour at room temperature with exclusion of moisture, the mixture was poured into 100 ml of water, the oil which had precipitated was extracted with ethyl acetate, the ethyl acetate solution was washed with water, dried over sodium 30-sulfate and evaporated. The 5 '- (3-anilino-2-cyanoallyl) -3' - (pyrrol-l-yl) -o-acetotoluidide of mp. Was obtained by column chromatography on silica gel with methylene chloride-ethyl acetate (9: 1) and recrystallization from ethanol. Get 218-220 °.
35 Eine Lösung von 0,94 g Natrium in 65 ml absolutem Äthanol wurde mit 3,85 g Guanidinhydrochlorid und 6,6 g 5'-(3-Anilino-2-cyanoallyl)-3'-(pyrrol-l-yl)-o-acetotoluidid versetzt und 20 Stunden unter Rückfluss und unter Stickstoff gekocht. Der Alkohol wurde im Vakuum entfernt, der 40 Rückstand in Wasser aufgenommen, abgesaugt und aus Methanol umkristallisiert. Das N-<alpha5-(2,4-Diamino-5-pyri-midinyl)-3-(pyrrol-l-yl)-2,5-xylyl>acetamid schmolz bei 110°. 35 A solution of 0.94 g sodium in 65 ml absolute ethanol was mixed with 3.85 g guanidine hydrochloride and 6.6 g 5 '- (3-anilino-2-cyanoallyl) -3' - (pyrrol-l-yl) - Added o-acetotoluidide and boiled under reflux and under nitrogen for 20 hours. The alcohol was removed in vacuo, the residue was taken up in water, suction filtered and recrystallized from methanol. The N- <alpha5- (2,4-diamino-5-pyrimidinyl) -3- (pyrrol-l-yl) -2,5-xylyl> acetamide melted at 110 °.
v v
Claims (3)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1728774A CH605828A5 (en) | 1974-12-24 | 1974-12-24 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH617191A5 true CH617191A5 (en) | 1980-05-14 |
Family
ID=4424233
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1728774A CH605828A5 (en) | 1974-12-24 | 1974-12-24 | |
| CH1499977A CH617191A5 (en) | 1974-12-24 | 1977-12-07 | Process for the preparation of novel benzylpyrimidines |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1728774A CH605828A5 (en) | 1974-12-24 | 1974-12-24 |
Country Status (25)
| Country | Link |
|---|---|
| JP (1) | JPS5191273A (en) |
| AT (1) | AT344704B (en) |
| AU (1) | AU500102B2 (en) |
| BE (1) | BE836996A (en) |
| BR (1) | BR7508534A (en) |
| CA (1) | CA1059127A (en) |
| CH (2) | CH605828A5 (en) |
| CU (1) | CU34406A (en) |
| DD (1) | DD123603A5 (en) |
| DE (1) | DE2558150A1 (en) |
| DK (1) | DK137797B (en) |
| ES (1) | ES443790A1 (en) |
| FI (1) | FI753312A (en) |
| FR (1) | FR2295750A1 (en) |
| GB (1) | GB1492140A (en) |
| HU (1) | HU174324B (en) |
| IL (1) | IL48416A (en) |
| LU (1) | LU73971A1 (en) |
| NL (1) | NL7514269A (en) |
| NO (1) | NO141408C (en) |
| PH (1) | PH12314A (en) |
| PL (1) | PL101046B1 (en) |
| SE (1) | SE417607B (en) |
| SU (1) | SU612629A3 (en) |
| ZA (1) | ZA756964B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GR71725B (en) * | 1977-11-10 | 1983-06-22 | Hoffmann La Roche | |
| AU2010284255B2 (en) | 2009-08-17 | 2016-11-17 | Memorial Sloan-Kettering Cancer Center | Heat shock protein binding compounds, compositions, and methods for making and using same |
| WO2015175707A1 (en) | 2014-05-13 | 2015-11-19 | Memorial Sloan Kettering Cancer Center | Hsp70 modulators and methods for making and using the same |
-
1974
- 1974-12-24 CH CH1728774A patent/CH605828A5/xx not_active IP Right Cessation
-
1975
- 1975-11-04 IL IL48416A patent/IL48416A/en unknown
- 1975-11-05 ZA ZA00756964A patent/ZA756964B/en unknown
- 1975-11-07 AU AU86433/75A patent/AU500102B2/en not_active Expired
- 1975-11-25 FI FI753312A patent/FI753312A/fi not_active Application Discontinuation
- 1975-11-29 CU CU7534406A patent/CU34406A/en unknown
- 1975-12-08 NL NL7514269A patent/NL7514269A/en not_active Application Discontinuation
- 1975-12-09 LU LU73971A patent/LU73971A1/xx unknown
- 1975-12-18 CA CA242,038A patent/CA1059127A/en not_active Expired
- 1975-12-19 HU HU75HO1864A patent/HU174324B/en unknown
- 1975-12-22 PH PH7517896A patent/PH12314A/en unknown
- 1975-12-22 JP JP50152026A patent/JPS5191273A/ja active Pending
- 1975-12-22 FR FR7539341A patent/FR2295750A1/en active Granted
- 1975-12-22 BR BR8534/75A patent/BR7508534A/en unknown
- 1975-12-22 SU SU752301512A patent/SU612629A3/en active
- 1975-12-22 AT AT975975A patent/AT344704B/en not_active IP Right Cessation
- 1975-12-23 DD DD190511A patent/DD123603A5/xx unknown
- 1975-12-23 BE BE163041A patent/BE836996A/en unknown
- 1975-12-23 GB GB52604/75A patent/GB1492140A/en not_active Expired
- 1975-12-23 DK DK589675AA patent/DK137797B/en unknown
- 1975-12-23 SE SE7514642A patent/SE417607B/en unknown
- 1975-12-23 DE DE19752558150 patent/DE2558150A1/en not_active Ceased
- 1975-12-23 PL PL1975185924A patent/PL101046B1/en unknown
- 1975-12-23 ES ES443790A patent/ES443790A1/en not_active Expired
- 1975-12-23 NO NO754372A patent/NO141408C/en unknown
-
1977
- 1977-12-07 CH CH1499977A patent/CH617191A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BR7508534A (en) | 1976-12-21 |
| FR2295750B1 (en) | 1980-06-20 |
| IL48416A (en) | 1980-02-29 |
| DK589675A (en) | 1976-06-25 |
| CA1059127A (en) | 1979-07-24 |
| ZA756964B (en) | 1976-10-27 |
| DK137797B (en) | 1978-05-08 |
| CU34406A (en) | 1978-09-08 |
| PH12314A (en) | 1979-01-16 |
| NO754372L (en) | 1976-06-25 |
| AU8643375A (en) | 1977-05-12 |
| BE836996A (en) | 1976-06-23 |
| SU612629A3 (en) | 1978-06-25 |
| CH605828A5 (en) | 1978-10-13 |
| NL7514269A (en) | 1976-06-28 |
| ES443790A1 (en) | 1977-12-16 |
| DK137797C (en) | 1978-10-16 |
| SE7514642L (en) | 1976-06-28 |
| AT344704B (en) | 1978-08-10 |
| AU500102B2 (en) | 1979-05-10 |
| IL48416A0 (en) | 1976-01-30 |
| HU174324B (en) | 1979-12-28 |
| FI753312A (en) | 1976-06-25 |
| ATA975975A (en) | 1977-12-15 |
| JPS5191273A (en) | 1976-08-10 |
| NO141408C (en) | 1980-03-05 |
| FR2295750A1 (en) | 1976-07-23 |
| DD123603A5 (en) | 1977-01-05 |
| NO141408B (en) | 1979-11-26 |
| SE417607B (en) | 1981-03-30 |
| GB1492140A (en) | 1977-11-16 |
| DE2558150A1 (en) | 1976-07-01 |
| LU73971A1 (en) | 1977-07-01 |
| PL101046B1 (en) | 1978-11-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0239907B1 (en) | Phenoxyalkanecarboxylic-acid derivatives, process for their preparation and medicines containing these compounds | |
| CH396924A (en) | Process for the preparation of 4-mercapto-pyrazolo (3,4-d) pyrimidines | |
| DE1954584A1 (en) | Process for the preparation of new heterocyclic compounds | |
| CH396923A (en) | Process for the preparation of 4-mercapto-pyrazolo (3,4-d) pyrimidines | |
| CH617191A5 (en) | Process for the preparation of novel benzylpyrimidines | |
| DE2443682C2 (en) | New 2,4-diamino-5-benzylpyrimidines | |
| AT356117B (en) | METHOD FOR PRODUCING NEW 2,4-DIAMINO-5-BENZYLPYRIMIDINES | |
| EP0088345B1 (en) | 2-aminomethyl-6-sulfamoylphenol derivatives, process for their preparation, their use and pharmaceutical preparations based on these compounds | |
| AT390952B (en) | METHOD FOR PRODUCING NEW FURANE OR THIOPHENE DERIVATIVES | |
| DE1695104A1 (en) | Active sulfonamides | |
| EP0012725B1 (en) | Quinoxaline-di-n-oxide derivatives, process for their preparation, compositions containing them and their use | |
| EP0213295A1 (en) | Thieno-1,2-thiazole derivatives, process for their preparation, and pharmaceutical compositions containing them | |
| DE1668137A1 (en) | Process for the production of new substituted cinnamic acids | |
| DE3245950A1 (en) | Process for the preparation of substituted pyridines | |
| AT351033B (en) | PROCESS FOR THE PRODUCTION OF NEW BENZYL PYRIMIDINES AND THEIR SALT | |
| AT237612B (en) | Process for the preparation of new imidazolinone and imidazolidinone derivatives | |
| AT226239B (en) | Process for the production of new benzylguanidines | |
| AT227706B (en) | Process for the preparation of new 4-mercapto-pyrazolo [3,4-d] pyrimidines | |
| AT282582B (en) | Process for the preparation of new, 3,4-disubstituted 5-sulfamylsalicylic acid anilide derivatives and their salts | |
| AT269150B (en) | Process for the preparation of new pteridine compounds | |
| AT222109B (en) | Process for the preparation of new 4-chloro-3-sulfamylbenzanilides and their alkali metal salts | |
| AT268272B (en) | Process for the production of new imidazole derivatives and their salts | |
| DE3121137A1 (en) | Novel pyridazino[4,5-b]indoles, processes for their preparation, their use and also pharmaceutical preparations based on these compounds, intermediates and their preparation | |
| DE3135728A1 (en) | Process for preparing apovincamine acid esters | |
| DE2161586A1 (en) | 5-nitrofuryl triazolopyridazines - microbicides, active against urinary tract infections |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |