DE1023465B - Process for the preparation of thiopyrimidine compounds - Google Patents
Process for the preparation of thiopyrimidine compoundsInfo
- Publication number
- DE1023465B DE1023465B DEF17863A DEF0017863A DE1023465B DE 1023465 B DE1023465 B DE 1023465B DE F17863 A DEF17863 A DE F17863A DE F0017863 A DEF0017863 A DE F0017863A DE 1023465 B DE1023465 B DE 1023465B
- Authority
- DE
- Germany
- Prior art keywords
- compounds
- methylpyrimidine
- journal
- dimethylamino
- thiopyrimidine
- 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.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 7
- HBCQSNAFLVXVAY-UHFFFAOYSA-N pyrimidine-2-thiol Chemical class SC1=NC=CC=N1 HBCQSNAFLVXVAY-UHFFFAOYSA-N 0.000 title claims description 3
- 238000002360 preparation method Methods 0.000 title description 2
- 239000000126 substance Substances 0.000 claims description 6
- -1 aralkyl mercaptans Chemical class 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 2
- 150000005694 halopyrimidines Chemical class 0.000 claims description 2
- 150000002170 ethers Chemical class 0.000 claims 1
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 241001465754 Metazoa Species 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 239000007795 chemical reaction product Substances 0.000 description 4
- 230000001085 cytostatic effect Effects 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- HJIUPFPIEBPYIE-UHFFFAOYSA-N Crimidine Chemical compound CN(C)C1=CC(C)=NC(Cl)=N1 HJIUPFPIEBPYIE-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- ZMRFRBHYXOQLDK-UHFFFAOYSA-N 2-phenylethanethiol Chemical compound SCCC1=CC=CC=C1 ZMRFRBHYXOQLDK-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 239000003610 charcoal Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 150000003230 pyrimidines Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- WWFIIZLHSNBNTC-UHFFFAOYSA-N (2-chlorophenyl)methanethiol Chemical compound SCC1=CC=CC=C1Cl WWFIIZLHSNBNTC-UHFFFAOYSA-N 0.000 description 1
- QLMHBOTXLHXVKY-UHFFFAOYSA-N (2-chlorophenyl)methylthiourea Chemical compound NC(=S)NCC1=CC=CC=C1Cl QLMHBOTXLHXVKY-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BASMANVIUSSIIM-UHFFFAOYSA-N 1-chloro-2-(chloromethyl)benzene Chemical compound ClCC1=CC=CC=C1Cl BASMANVIUSSIIM-UHFFFAOYSA-N 0.000 description 1
- UIFIGYAGINMIDI-UHFFFAOYSA-N 2,5-dichloro-N,N,6-trimethylpyrimidin-4-amine Chemical compound ClC1=NC(=C(C(=N1)N(C)C)Cl)C UIFIGYAGINMIDI-UHFFFAOYSA-N 0.000 description 1
- UNIQGWYGYQXIEY-UHFFFAOYSA-N 2-benzylsulfanyl-6-methylpyrimidin-4-amine Chemical compound CC1=CC(N)=NC(SCC=2C=CC=CC=2)=N1 UNIQGWYGYQXIEY-UHFFFAOYSA-N 0.000 description 1
- OUSLKOVFFKQOQS-UHFFFAOYSA-N 2-chloro-4-methyl-6-piperidin-1-ylpyrimidine Chemical compound ClC1=NC(C)=CC(N2CCCCC2)=N1 OUSLKOVFFKQOQS-UHFFFAOYSA-N 0.000 description 1
- JZPSTWTXSVNRFD-UHFFFAOYSA-N 2-chloro-6-ethyl-n,n-dimethylpyrimidin-4-amine Chemical compound CCC1=CC(N(C)C)=NC(Cl)=N1 JZPSTWTXSVNRFD-UHFFFAOYSA-N 0.000 description 1
- IUAXXCMQELIWQC-UHFFFAOYSA-N 2-chloro-n,n,5,6-tetramethylpyrimidin-4-amine Chemical compound CN(C)C1=NC(Cl)=NC(C)=C1C IUAXXCMQELIWQC-UHFFFAOYSA-N 0.000 description 1
- OMPXZZNLSYCISQ-UHFFFAOYSA-N 2-chloro-n,n,5-trimethylpyrimidin-4-amine Chemical compound CN(C)C1=NC(Cl)=NC=C1C OMPXZZNLSYCISQ-UHFFFAOYSA-N 0.000 description 1
- MTEQLYDOCFPCAX-UHFFFAOYSA-N 2-chloro-n,n-dimethylpyrimidin-4-amine Chemical compound CN(C)C1=CC=NC(Cl)=N1 MTEQLYDOCFPCAX-UHFFFAOYSA-N 0.000 description 1
- LVCHGNHQESCABQ-UHFFFAOYSA-N 4-chloro-2-[(2-chlorophenyl)methylsulfanyl]-6-methylpyrimidine Chemical compound CC1=CC(Cl)=NC(SCC=2C(=CC=CC=2)Cl)=N1 LVCHGNHQESCABQ-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- GLJCFLNZDJSOAY-UHFFFAOYSA-N Cl.ClC1=C(CSC2=NC=CC(=N2)N(C)C)C=CC=C1 Chemical compound Cl.ClC1=C(CSC2=NC=CC(=N2)N(C)C)C=CC=C1 GLJCFLNZDJSOAY-UHFFFAOYSA-N 0.000 description 1
- RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical class S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- UENWRTRMUIOCKN-UHFFFAOYSA-N benzyl thiol Chemical compound SCC1=CC=CC=C1 UENWRTRMUIOCKN-UHFFFAOYSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000824 cytostatic agent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- LBAQSKZHMLAFHH-UHFFFAOYSA-N ethoxyethane;hydron;chloride Chemical compound Cl.CCOCC LBAQSKZHMLAFHH-UHFFFAOYSA-N 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung von Thiopyrimidinverbindungen Es wurde gefunden, daß man wertvolle neue Thiopyrimidinverbirdurgen erhält, wenn man entweder 2-Halogen-4-aminopyrimidine, in denen die Aminogruppe tertiär ist, mit gegebenenfalls substituierten Aralkylmercaptanen umsetzt cder wenn man gegebenenfalls substituierte Isothioharnstoffarall,#yläther mit ß-Ketocarbonsäureestern kondensiert, die entstandenen 4-Oxypyrimidine zu Halogenpyrimidinen halogeniert und diese mit sekundären Aminen umsetzt.Process for the preparation of thiopyrimidine compounds It has been found that you get valuable new Thiopyrimidinverbirdurgen if you either 2-halo-4-aminopyrimidines, in which the amino group is tertiary, with optionally substituted aralkyl mercaptans converts if optionally substituted isothioureaarall, # ylether condensed with ß-ketocarboxylic acid esters, the resulting 4-oxypyrimidines to halopyrimidines halogenated and this reacts with secondary amines.
Die erfindungsgemäß erhältlichen Verbindungen haben die allgemeine Formel worin R, und R2 Alkylgruppen, die auch mit dem Stickstoffatom zum heterocyclischen Ring geschlossen sein können, R;, einen Wasserstoff- oder einen Alkylrest oder Halogenatom, R,, ein Wasserstoffatom oder einen Alkylrest bedeuten.The compounds obtainable according to the invention have the general formula in which R 1 and R 2 are alkyl groups which can also be closed with the nitrogen atom to form the heterocyclic ring, R 1 denotes a hydrogen or an alkyl radical or a halogen atom, R 1 denotes a hydrogen atom or an alkyl radical.
Die so erhaltenen Verbindungen sind pharmakologisch von Interesse und zei-en insbesondere eine bemerkenswerte cytostatische Wirkung.The compounds thus obtained are of pharmacological interest and in particular show a remarkable cytostatic effect.
Beispiel 1 17,2 Teile 2-Chlor-4-dimethylamino-6-methylpyrimidin und 12,4 Teile Benzylmercaptan werden auf 195' erhitzt. Dabei tritt eine Reaktion ein, und die Innentemperatur steigt auf 240°. Das in der Kälte erstarrte Reaktionsprodukt wird aus Alkohol umgelöst. Es werden 16 Teile 2-Benzylmercapto-4-dimethylamino-6-methyl-pyrimidinhy drochlorid als weißes kristallines Pulver erhalten. Es schmilzt bei 194'.Example 1 17.2 parts of 2-chloro-4-dimethylamino-6-methylpyrimidine and 12.4 parts of benzyl mercaptan are heated to 195 '. A reaction occurs and the internal temperature rises to 240 °. The reaction product solidified in the cold is dissolved from alcohol. There are 16 parts of 2-benzylmercapto-4-dimethylamino-6-methyl-pyrimidinhy obtained drochloride as a white crystalline powder. It melts at 194 '.
Beispiel 2 21,2 Teile 2-Chlor-4-piperidino-6-methylpyrimidin und 15,9 Teile ö-Chlorbenzylmercaptan werden bei 210' miteinander verschmolzen. Das Reaktionsprodukt wird heiß in Alkohol gelöst und vorsichtig mit Äther gefällt. Es werden 25,1 Teile 2-o-Chlorbenzylmercapto-4-piperidino-6-methylpyrimidinhydrochlorid vom Schmelzpunkt 201 bis 203' als weißes kristallines Pulver erhalter.Example 2 21.2 parts of 2-chloro-4-piperidino-6-methylpyrimidine and 15.9 Parts of δ-chlorobenzyl mercaptan are fused together at 210 '. The reaction product is dissolved hot in alcohol and carefully precipitated with ether. It will be 25.1 parts 2-o-chlorobenzylmercapto-4-piperidino-6-methylpyrimidine hydrochloride of melting point 201 to 203 'obtained as a white crystalline powder.
Beispiel 3 12,3 Teile 2-Chlor-4-dimethylaminopyrimidin und 12,4 Teile o-Chlorbenzylmercaptan werden, wie im Beispiel 1 angegeben, miteinander verschmolzen. Die Schmelze wird aus verdünntem Alkohol umkristallisiert. Es werden 10,4 Teile 2-o-Chlorbenzylmercapto-4-dimethylaminopyrimidin-liydrochlorid vom Schmelzpunkt 233' erhalten. Auf ähnliche Weise werden erhalten: 2-o-Chlorbenzylmcrcapto-4-dimethylamino-5-methylpyrimidinhydrochlorid, F. 216', aus 2-Chlor-4-dimethylamino-5-methylpyrimidin, Kp.; 161'; 2 - o - Chlorbenzylmercap to -4 - dimethylamino -6 -äthylpyrimidin-hydrochlorid, F. 207', aus 2-Chlor-4-dimethylamino-6-äthylpyrimidin, Kp.2127°; 2-o-Chlorbenzylmercap to -4-dimethylamino-5,6 -dimethylpyrimidinhydrochlorid, F. 238`-', aus 2-Chlor-4-dimethylamino-5,6-dimetIiylpyrimidin, Kp.2128'; 2-p-Chlorbenzylmercap Lo-4-dimethylamino-6-methylpyrimidinhydrochlorid, F.221'; 2-m-Chlor benzylmercapto-4-dimethy lamino-6-methylpyrimidinhydrochloiid, F. 172'; 2 - o - Chlor benzylmercapto -4- dimethylamin o - 5 - chlor-6-methylpyrimidinhydrochlorid, F. 174' aus 2,5-Dichlor-4-dimethylamino-6-methylpyrimidin, F. 77'.Example 3 12.3 parts of 2-chloro-4-dimethylaminopyrimidine and 12.4 parts As indicated in Example 1, o-chlorobenzyl mercaptan is fused with one another. The melt is recrystallized from dilute alcohol. It will be 10.4 parts 2-o-chlorobenzylmercapto-4-dimethylaminopyrimidine hydrochloride of melting point 233 'received. In a similar way are obtained: 2-o-chlorobenzylmcrcapto-4-dimethylamino-5-methylpyrimidine hydrochloride, F. 216 ', from 2-chloro-4-dimethylamino-5-methylpyrimidine, bp .; 161 '; 2 - o - chlorobenzyl mercap to -4 - dimethylamino -6-ethylpyrimidine hydrochloride, F. 207 ', from 2-chloro-4-dimethylamino-6-ethylpyrimidine, B.p. 2127 °; 2-o-chlorobenzyl mercapto -4-dimethylamino-5,6 -dimethylpyrimidine hydrochloride, F. 238`- ', from 2-chloro-4-dimethylamino-5,6-dimethylpyrimidine, bp 2128'; 2-p-chlorobenzyl mercap Lo-4-dimethylamino-6-methylpyrimidine hydrochloride, F.221 '; 2-m-chloro benzylmercapto-4-dimethy lamino-6-methylpyrimidine hydrochloride, m.p. 172 '; 2 - o - chlorine benzyl mercapto -4- dimethylamine o - 5 - chloro-6-methylpyrimidine hydrochloride, F. 174 'from 2,5-dichloro-4-dimethylamino-6-methylpyrimidine, F. 77 '.
Beispiel 4 13,8 Teile ß-Phenyläthylmercaptan und 17,1 Teile 2-Chlor-4-dimethylamino-6-methylpyrimidin werden bei 200' miteinander verschmolzen, wobei eine milde Reaktion eintritt. Das Reaktionsprodukt wird warm in Alkohol aufgenommen und mit INTatronlauge alkalisch gemacht. Nach Zusatz von Wasser wird mit Methylenchlorid ausgeschüttelt. Nach Verdampfen des Methylenchlorids aus der wasserfreien Lösung wird der Rückstand destilliert: Bei Kp.4 222' geht das 2-ß-Phenyläthylmercapto-4-dimethylamino-6-methylpyrimidin als wasserhelles Öl über, das nach einiger Zeit erstarrt. Ausbeute 15,8 Teile.Example 4 13.8 parts of β-phenylethyl mercaptan and 17.1 parts of 2-chloro-4-dimethylamino-6-methylpyrimidine are fused together at 200 'with a mild reaction. That Reaction product is taken up warm in alcohol and alkaline with INT sodium hydroxide solution made. After adding water, it is extracted by shaking with methylene chloride. After evaporation of the methylene chloride from the anhydrous solution, the residue is distilled: At bp 4 222 'the 2-ß-phenylethylmercapto-4-dimethylamino-6-methylpyrimidine goes as a water-white oil that solidifies after a while. Yield 15.8 parts.
Beispiel 5 11,7 g o-Chlorbenzylisothioharnstoffäther-hydrochlorid (F. 196', dargestellt aus o-Chlorbenzylchlorid und Thioharnstoff ), 100 cm3 absoluter Alkohol und 6,5 g Acetessigester werden mit Eis gekühlt und langsam mit einer Lösung von 2,3 g Natrium in 100 ccm absolutem Alkohol versetzt. Nach 10 Stunden wird 2 Stunden unter Rückfluß gekocht und darauf das Lösemittel im Vakuum abdestilliert. Der Rückstand wird in warmem Wasser aufgenommen, mit Tierkohle geklärt und mit Ammoniumchloridlösung ausgefällt. Man erhält Kristalle des 2-o-Chlorbenzylmercapto-4-oxy-6-methylpyrimidins, die nach dem Umkristallisieren aus Alkohol bei 206Q schmelzen. 77 g dieser Verbindung werden mit 50 cm3 Phosphoroxychlorid etwa 1 Stunde gekocht. Das überschüssige Phosphoroxychlorid «wird unter vermindertem Druck abdestilliert und der Rückstand nach dem Zerlegen mit Wasser in Methylenchlorid aufgenommen. Nach Verdampfen des äJethylenchlorids aus der wasserfreien Lösung wird der Rückstand destilliert: Bei Kp.3 190' geht das 2-o-Chlorbenzylmercapto-4-chlor-6-methylpyrimidin als schnell kristallisierendes Öl über. 6,4 g dieses Chlorides werden mit 40 cm3 Alkohol und 20 cm3 10-n-Dimethylaminlösung 7 Stunden im Autoklav auf 100 bis 110° erhitzt. Das Reaktionsprodukt wird auf dem Wasserbad vom Lösungsmittel befreit, heiß in verdünnter Salzsäure aufgenommen und mit Tierkohle geklärt. Beim Abkühlen fallen weiße Kristalle des 2-o-Chlorbenzylmercapto - 4 - dimethylamino - 6 - methylpy rimidinhydrochlorids aus, die bei 226° schmelzen. Beispiel 6 17,2 g 2-Chlor-4-dimethylamino-6-methy lpyrimidin und 13,8 g ß-Phenyläthylmercaptanwerden in 150 ccm Pyridin gelöst und tropfenweise mit einer Lösung von 5 g Natriumhydroxyd in 10 ccm Wasser versetzt. Durch Kühlung wird die Temperatur unterhalb 30° gehalten. Nach einigen Stunden wird 30 Minuten auf 60 bis 70" erwärmt. Das Reaktionsgemisch wird darauf bei vermindertem Druck vom Pyridin befreit, der Rückstand mit Salzsäure kongosauer gemacht und vom Ausgangsmaterial mit Äther befreit. Die salzsaure Lösung wird alkalisch gestellt und mit Äther extrahiert. Nach Verdampfen des Äthers aus der wasserfreien Lösung wird der Rückstand destilliert, er siedet bei Kp.2 205 bis 208°. Man erhält das 2-ß-Phenyläthylmercapto-4-dimethylamino-6-methylpyrimidin als helles, bald erstarrendes Öl.Example 5 11.7 g of o-chlorobenzylisothiourea ether hydrochloride (F. 196 ', prepared from o-chlorobenzyl chloride and thiourea ), 100 cm3 of absolute alcohol and 6.5 g of acetoacetic ester are cooled with ice and slowly a solution of 2.3 g of sodium in 100 cc of absolute alcohol is added. After 10 Hours is refluxed for 2 hours and then the solvent in vacuo distilled off. The residue is taken up in warm water and clarified with animal charcoal and precipitated with ammonium chloride solution. Crystals of 2-o-chlorobenzylmercapto-4-oxy-6-methylpyrimidine are obtained, which melt at 206Q after recrystallization from alcohol. 77 g of this compound are boiled with 50 cm3 of phosphorus oxychloride for about 1 hour. The excess phosphorus oxychloride «Is distilled off under reduced pressure and the residue after decomposition taken up with water in methylene chloride. After evaporation of the ethylene chloride the residue is distilled from the anhydrous solution: at b.p. 3 190 'it works 2-o-chlorobenzylmercapto-4-chloro-6-methylpyrimidine as a rapidly crystallizing Oil over. 6.4 g of this chloride are mixed with 40 cm3 of alcohol and 20 cm3 of 10-n-dimethylamine solution Heated to 100 to 110 ° in the autoclave for 7 hours. The reaction product is on the Water bath freed from solvent, taken up hot in dilute hydrochloric acid and Clarified with animal charcoal. White crystals of 2-o-chlorobenzyl mercapto fall on cooling - 4 - dimethylamino - 6 - methylpyimidine hydrochloride, which melt at 226 °. Example 6 17.2 g of 2-chloro-4-dimethylamino-6-methylpyrimidine and 13.8 g of β-phenylethyl mercaptan become dissolved in 150 cc of pyridine and added dropwise with a solution of 5 g of sodium hydroxide mixed in 10 cc of water. The temperature is kept below 30 ° by cooling. After a few hours, the temperature is raised to 60 to 70 "for 30 minutes. The reaction mixture is then freed from pyridine under reduced pressure, the residue with hydrochloric acid made Congo acidic and freed from the raw material with ether. The hydrochloric acid solution is made alkaline and extracted with ether. After evaporation of the ether off the anhydrous solution, the residue is distilled, it boils at b.p. 2 205 bis 208 °. The 2-ß-phenylethylmercapto-4-dimethylamino-6-methylpyrimidine is obtained as light, soon solidifying oil.
Es ist zwar aus Journal of the Organic Chernistry, Bd.14 (1949), S. 236, Absatz 4, und aus der britischen Patentschrift 658 202, S. 5, Zeile 116, S. 6, Zeile 1, bekannt, ringständige Halogenatome in Pyrimidinabkömmlingen dadurch gegen eine verätherte Thiolgruppe auszutauschen, daß man derartige Pyrimidinverbindungen mit entsprechenden Mercaptanen umsetzt. Es ist ferner bekannt, 2-Aralkylthio-4-oxy-6-alkylpyrimidinderivate durch Kondensation von S-Aralkvlisothioharnstcffen mit ß-Ketocarbonsäureestern herzustellen (Journal of the American Chemical Society, Bd. 72 [1950], S. 3282, rechte Spalte, Zeile 11 bis 21). Schließlich ist aus Journal of the Chemical Society, 1950, S.457ff., bekannt, daß man Oxyverbindungen durch Behandlung mit Halogenierungsmitteln und Umsetzung der so entstandenen Halogenpyrimidinverbindungen mit primären oder sekundären Aminen in die entsprechenden Aminoverbindungen überführen kann.It is from the Journal of the Organic Chemistry, Volume 14 (1949), pp. 236, paragraph 4, and from British Patent Specification 658 202, p. 5, line 116, p. 6, line 1, known, ring halogen atoms in pyrimidine derivatives thereby to exchange for an etherified thiol group that such pyrimidine compounds with corresponding mercaptans. It is also known to use 2-aralkylthio-4-oxy-6-alkylpyrimidine derivatives to be prepared by condensation of S-Aralkvlisothiourstcffen with ß-ketocarboxylic acid esters (Journal of the American Chemical Society, Vol. 72 [1950], p. 3282, right column, Lines 11 to 21). Finally, from Journal of the Chemical Society, 1950, pp.457ff., known that oxy compounds by treatment with halogenating agents and Implementation of the resulting halopyrimidine compounds with primary or secondary ones Can convert amines into the corresponding amino compounds.
Bei Anwendung all dieser bekannten Verfahren erhält man jedoch Verbindungen, die keinen merklichen cytostatischen Effekt aufweisen. Der Vorteil des erfindungsgemäßen Verfahrens liegt demgegenüber darin, daß die nach diesem hergestellten Verbindungen diesen Effekt in hohem Maße besitzen.However, when all of these known methods are used, compounds are obtained which have no noticeable cytostatic effect. The advantage of the invention Process is in contrast to the fact that the compounds produced according to this have this effect to a great extent.
Zum Nachweis der größeren cytostatischen Wirksamheit der Verfahrensprodukte gegenüber bekannten analogen Verbindungen wurde das verfahrensgemäß erhältliche 2-Benzylmercapto-4-dimethyiamino-6-methylpyrimidin (I) mit dem aus -Bulletin de la societe chimique de France-, 1948, S. 392ff. (referiert in -Chemical Abstracts, Bd.42 ,"1948', Spalte 5916 i), bekannten 2-Benzylmercapto-4-amino-6-methylpyrimidin (II) verglichen.To demonstrate the greater cytostatic effectiveness of the products of the process compared to known analogous compounds, the one obtainable according to the process became 2-Benzylmercapto-4-dimethyiamino-6-methylpyrimidine (I) with the one from Bulletin de la societe chimique de France-, 1948, p. 392ff. (reported in -Chemical Abstracts, Vol. 42, "1948 ', column 5916 i), known 2-benzylmercapto-4-amino-6-methylpyrimidine (II) compared.
Zu diesem Zweck wurden je sechzehn Mäuse, die mit Ehrlich-Carcinomen behaftet «-aren, mit 0,1°,'oigen und 1°,!oigen Lösungen von I bzw. II behandelt. Bei den mit I behandelten Tieren waren nach der Behandlung elf Tiere vollkommen frei von Tumoren, bei vier Tieren waren die Tumore noch vorhanden, und ein Tier war tot. Bei den mit II behandelten Tieren waren nach der Behandlung nur vier tumorfrei. Bei elf Tieren waren die Tumore noch vorhanden, und ein Tier war tot.For this purpose, sixteen mice each with Ehrlich's carcinoma were tested afflicted «-aren, treated with 0.1 °, oigen and 1 °, oigen solutions of I and II, respectively. In the animals treated with I, eleven animals were perfect after treatment free of tumors, the tumors were still present in four animals, and one animal was dead. Only four of the animals treated with II were tumor-free after treatment. In eleven animals, the tumors were still present and one animal was dead.
Diese Versuche zeigen, daß die cytostatische Wirkung von I wesentlich größer ist als die von II.These experiments show that the cytostatic effect of I is essential is greater than that of II.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEF17863A DE1023465B (en) | 1955-07-05 | 1955-07-05 | Process for the preparation of thiopyrimidine compounds |
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| Application Number | Priority Date | Filing Date | Title |
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| DEF17863A DE1023465B (en) | 1955-07-05 | 1955-07-05 | Process for the preparation of thiopyrimidine compounds |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1114197B (en) | 1959-04-17 | 1961-09-28 | Bayer Ag | Process for the preparation of quaternized 2-mercapto-4-aminopyrimidine compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB658202A (en) * | 1948-11-05 | 1951-10-03 | Arthur Donald Ainley | New pyrimidine derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB658202A (en) * | 1948-11-05 | 1951-10-03 | Arthur Donald Ainley | New pyrimidine derivatives |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1114197B (en) | 1959-04-17 | 1961-09-28 | Bayer Ag | Process for the preparation of quaternized 2-mercapto-4-aminopyrimidine compounds |
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