SE450120B - NEW DIMETOXICINAZOLINE DERIVATIVES TO USE FOR PREPARATION OF 2 (4-SUBSTITUTED PIPERAZIN-1-YL) -4-AMINO-6,7-DIMETOXICINAZOLINES - Google Patents
NEW DIMETOXICINAZOLINE DERIVATIVES TO USE FOR PREPARATION OF 2 (4-SUBSTITUTED PIPERAZIN-1-YL) -4-AMINO-6,7-DIMETOXICINAZOLINESInfo
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4
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Description
J§~ (f: c? ÉÄÉ ï 2 och motsvarande 6,7,8-trimetoxikinazoliner enligt förfaranden, som antingen innefattar: (1) reaktion av den lämpliga 4,5-di- metoxisubstituerade eller 3,4,5-trimetoxi-substituerade 2-amino- bensonitrilen med vissa 1,4-disubstituerade piperaziner; eller (2) reaktion av den lämpliga 4,5-dimetoxi- eller 3,4,5-trimetoxi- substituerade 2-aminobensamidinen med samma 1,4-disubstituerade piperaziner. And the corresponding 6,7,8-trimethoxyquinazolines according to methods, which comprise either: (1) reaction of the appropriate 4,5-dimethoxy-substituted or 3,4,5-trimethoxy- substituted 2-aminobenzonitrile with certain 1,4-disubstituted piperazines, or (2) reaction of the appropriate 4,5-dimethoxy- or 3,4,5-trimethoxy-substituted 2-aminobenzamidine with the same 1,4-disubstituted piperazines .
Föreningar med formlerna: CH O N Cl CH O / \ 3 <;>r/f 3\\ I, \\ N _Y , \| /1 \ / CH30 C33 HQHZCGHS NHCH2C6H5 vari Y är väte, alkyl med l-5 kolatomer, hydroxialkyl med 2- 5 kolatomer, alkanoyl med 2-7 kolatomer, allylpropargyl, 2- metallyl, fenyl, bensyl, bensoyl, klorobensoyl, bromobensoyl, trifluorometyl, metoxifenyl, metylfenyl, metylbensoyl, trifluor- metylbensoyl, furoyl, bensofuroyl, tenoyl, pyridinkarbonyl, 3,4,5- trimetoxibensoyl, karboxylsyraalkylester, vari alkylen innehåller l-6 kolatomer och karboxylsyraalkenylester, vari alkenylen inne- håller 3-6 kolatomer, anges i den amerikanska patentskriften 3.511.836. Emellertid utgör andra intermediat nya föreningar, såsom de enligt föreliggande uppfinning.Compounds of the formulas: CH O N Cl CH O / \ 3 <;> r / f 3 \\ I, \\ N _Y, \ | Wherein Y is hydrogen, alkyl of 1-5 carbon atoms, hydroxyalkyl of 2-5 carbon atoms, alkanoyl of 2-7 carbon atoms, allylpropargyl, 2-methallyl, phenyl, benzyl, benzoyl, chlorobenzoyl, bromobenzoyl, trifluoromethyl, methoxyphenyl, methylphenyl, methylbenzoyl, trifluoromethylbenzoyl, furoyl, benzofuroyl, tenoyl, pyridinecarbonyl, 3,4,5-trimethoxybenzoyl, carboxylic acid alkyl ester, wherein the alkylene contains 1-6 carbon atoms and carboxylic acid alkenyl ester containing disclosed in U.S. Patent 3,511,836. However, other intermediates are novel compounds, such as those of the present invention.
Patentet 7705745-3 (publ.nr 435 380) avser ett förfarande för framställning av en förening, som har formeln R 1 / \ cH3o N N N'R2 Y! // ...(I) cH3o _ H2 -fa -P LN J ><_\ bâ CD vari Rl är väte och R2 är furoyl, eller ett hydroklorid- eller hydrobromid-syraadditionssalt därav, vilket utmärkes därav, att (a) en mol av en första reaktant, som har formeln H cH o X 3 y / cH3o \ ...(II) R3/ R4 vari X är klor eller brom; R3 är väte och R4 är -COOCH2C6H4R5, -C0R6, -COCF3, -CHO eller COOR6, eller R3 och R4 tillsammans med den kväveatom, vartill de är bundna, bildar en ftalimidogrupp; R5 är väte, klor, brom, metyl, metoxi eller nitro; och R6 är alkyl med l-4 kolatomer eller -C6H4R5, bringas att reagera med 2 mol av en andra reaktant, som har formeln HN N-Rz \ / ...(III) vari R2 är furoyl, i ett reaktionsinert organiskt lösningsmedel vid en temperatur från 80 till l30°C; eller (b) en förening, som har formeln (II), vari R3 och R4 tillsammans med den kväveatom, vartill de är bundna, bildar en ftalimido- grupp, bringas att reagera med en ekvimolär mängd av en förening, som har formeln (III), i ett reaktionsinert lösningsmedel vid en temperatur från 80 till l30°C, till bildning av ett inter- mediat, som har formeln: JB LI| CD ....\ hö CD ...(1v) och att detta intermediat vidare bringas att reagera genom syrahydrolïs till bildning av den önskade slutprodukten med formeln (I).Patent 7705745-3 (Publ. No. 435 380) relates to a process for the preparation of a compound having the formula R 1 / \ cH 30 N N N'R 2 Y! // ... (I) cH 30 _ H 2 -fa -P LN J> <_ \ bâ CD wherein R 1 is hydrogen and R 2 is furoyl, or a hydrochloride or hydrobromic acid addition salt thereof, which is characterized in that (a) a mole of a first reactant having the formula H cH o X 3 y / cH 30 \ ... (II) R 3 / R 4 wherein X is chlorine or bromine; R 3 is hydrogen and R 4 is -COOCH 2 C 6 H 4 R 5, -COR 6, -COCF 3, -CHO or COOR 6, or R 3 and R 4 together with the nitrogen atom to which they are attached form a phthalimido group; R 5 is hydrogen, chlorine, bromine, methyl, methoxy or nitro; and R 6 is alkyl of 1-4 carbon atoms or -C 6 H 4 R 5, reacted with 2 moles of a second reactant having the formula HN N-R 2 / ... (III) wherein R 2 is furoyl, in a reaction-inert organic solvent at a temperature of from 80 to 130 ° C; or (b) a compound having the formula (II), wherein R 3 and R 4 together with the nitrogen atom to which they are attached form a phthalimido group, are reacted with an equimolar amount of a compound having the formula (III ), in a reaction-inert solvent at a temperature of from 80 to 130 ° C, to give an intermediate having the formula: JB LI | CD .... \ hö CD ... (1v) and that this intermediate is further reacted by acid hydrolysis to give the desired final product of formula (I).
Det kända hypotensiva medlet med formeln I Ovan, nämligen 2-/4- (2-furoyl)piperazin-l-yl/-4-amino-6,7-dimetoxikinazolin, är känt inom tekniken såsom prazosin. Prazosin har nyligen rappor- terats såsom havande terapeutisk användbarhet på människa (Cohen, Journal of Clinical Pharmacology, lg, 408 /1970; De Guia, et al., Current Therapeutic Research, lä, 339 /l973/).The known hypotensive agent of the formula I Above, namely 2- / 4- (2-furoyl) piperazin-1-yl / -4-amino-6,7-dimethoxyquinazoline, is known in the art as prazosin. Prazosin has recently been reported as having therapeutic utility in humans (Cohen, Journal of Clinical Pharmacology, lg, 408/1970; De Guia, et al., Current Therapeutic Research, lä, 339 / l973 /).
Enligt föreliggande uppfinning åstadkommes ett nytt intermediat, som användes vid förfarandet ovan för framställning av en produkt med formeln I, vilket utmärkes därav, att det har formeln gg/N\\R4 ...(II) 4 är -COOCH2C6H4R5, 6, -COCF3, -CHO eller -COORG eller R3 och R4 tillsammans vari X är klor eller brom, R3 är väte och R -COR med den kväveatom vartill de är bundna bildar en ftalimidogrupp; R5 är väte, klor, brom, metyl, metoxi eller nitro och R6 är alkyl med l-4 kolatomer eller -C H R samt syraadditionssalter 6 4 5' därav.According to the present invention there is provided a novel intermediate used in the above process for the preparation of a product of formula I, which is characterized in that it has the formula gg / N \\ R4 ... (II) 4 is -COOCH2C6H4R5, 6, - COCF 3, -CHO or -COORG or R 3 and R 4 together wherein X is chlorine or bromine, R 3 is hydrogen and R 1 -COR with the nitrogen atom to which they are attached form a phthalimido group; R 5 is hydrogen, chlorine, bromine, methyl, methoxy or nitro and R 6 is alkyl of 1-4 carbon atoms or -C H R and acid addition salts thereof.
Föredragna föreningar enligt uppfinningen är de, vari X är klor.Preferred compounds of the invention are those wherein X is chlorine.
Följande exempel l, 3, 4 och 5 belyser framställning av nya intermediat enligt uppfinningen. Exempel 2, 6 och 7 belyser fram- ställning av prazosin med användning av utvalda intermediat enligt uppfinningen.The following examples 1, 3, 4 and 5 illustrate the preparation of novel intermediates according to the invention. Examples 2, 6 and 7 illustrate the preparation of prazosin using selected intermediates of the invention.
Exempel l 2-kloro-4-ftalimido-6,7-dimetoxikinazolin En 100 ml trehalsad, rundbottnad kolv försedd med termometer, omrörare och torkrör beskickades med SO ml N,N-dimetylformamid, 1,47 9 (0,0lO mol) ftalimid och 0,48 g (0,0lO mol) 50%-ig (vikt/vikt) natriumhydrid. Efter omröring vid rumstemperatur i 30 minuter erhölls en klar lösning. Därtill sattes 2,59 g (0,0lO mol) 2,4-dikloro-6,7-dimetoxikinazolin och den erhållna blandningen upphettades vid lO0°C i 5 timmar. Reaktionsbland- ningen kyldes till rumstemperatur, 150 ml vatten tillsattes och den fällda produkten isolerades genom filtrering och torka- des i vakuum för erhâllning av 3,1 g av titelföreningen, smält- punkt 255°C. Strukturen verifierades medelst NMR och masspektral- data. Utbyte 84 %.Example 1 2-Chloro-4-phthalimido-6,7-dimethoxyquinazoline A 100 ml three-necked, round-bottomed flask equipped with a thermometer, stirrer and drying tube was charged with 50 ml of N, N-dimethylformamide, 1.47 g (0.010 mol) of phthalimide and 0.48 g (0.010 mol) of 50% (w / w) sodium hydride. After stirring at room temperature for 30 minutes, a clear solution was obtained. To this was added 2.59 g (0.010 mol) of 2,4-dichloro-6,7-dimethoxyquinazoline and the resulting mixture was heated at 10 ° C for 5 hours. The reaction mixture was cooled to room temperature, 150 ml of water were added and the precipitated product was isolated by filtration and dried in vacuo to give 3.1 g of the title compound, m.p. 255 ° C. The structure was verified by NMR and mass spectral data. Yield 84%.
Exempel 2 (a) 2-/4-(2-furoyl)-piperazin-l-yl/-4-ftalimido-6,7-dimetoxi- kinazolin En 35 ml enhalsad, rundbottnad kolv, försedd med kylare och torkrör, beskickades med 1,0 g (0,0027 mol) 2-kloro-4-ftalimido- -6,7-dimetoxikinazolin, 10 ml isoamylalkohol och en lösning av 0,550 g (0,003 mol) l-(2-furoyl)piperazin. Den erhållna bland- ningen upphettades vid l30°C i 4 timmar, kyldes därefter till rumstemperatur. Till reaktionsblandningen sattes 35 ml hexan och den fällda produkten tillvaratogs genom filtrering och torkades för erhållning av 0,70 g (47 %) av hydrokloridsaltet av titelföreningen. Den renade fria basen erhölls ur saltet genom kiselgelkromatografi på en 5 x 30 cm kolonn och eluering med etylacetat/dietylamin (90,l0). Den renade produkten smälte vid 3o5°c.Example 2 (a) 2- [4- (2-furoyl) -piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline A 35 ml single neck round bottom flask equipped with a condenser and drying tube was charged with 1.0 g (0.0027 mol) of 2-chloro-4-phthalimido-6,7-dimethoxyquinazoline, 10 ml of isoamyl alcohol and a solution of 0.550 g (0.003 mol) of 1- (2-furoyl) piperazine. The resulting mixture was heated at 130 ° C for 4 hours, then cooled to room temperature. To the reaction mixture was added 35 ml of hexane, and the precipitated product was collected by filtration and dried to obtain 0.70 g (47%) of the hydrochloride salt of the title compound. The purified free base was obtained from the salt by silica gel chromatography on a 5 x 30 cm column and eluting with ethyl acetate / diethylamine (90, 10). The purified product melted at 30 ° C.
När förfarandet ovan upprepades men med användning av det angivna lösningsmedlet istället för isoamylalkohol och vid den angivna temperaturen och reaktionstiden erhölls likaledes titelföreningen.When the above procedure was repeated but using the indicated solvent instead of isoamyl alcohol and at the indicated temperature and reaction time, the title compound was also obtained.
Lösningsmedel Reaktionstemperatur Reaktionstid OC timmar isobutanol 50 48 1,2-dimetoxietan ' a 80 30 dietylenglykolmonoetyleter 200 1 (b) 2-/4-(2-furoyl)piperazin-l-yl/-4-amino-6,7-dimetoxíkinazolin En lösning av 95 mg (O,l85 mmol) 2-/4-(2-furoyl)-piperazin-l-yl/- '-4-ftalimido-6.7-dimetoxikinazolin i 2,0 ml koncentrerad klor- vätesyra omrördes vid rumstemperatur i 2 timmar. Därefter till- sattes 4,0 ml kloroform och blandningen inställdes på pH 10 genom tillsats av natriumkarbonatlösning. Kloroformskiktet separerades och indunstades till torrhet för erhàllning av 55 mg (77,6 %) 2-/4-(2-furoyl)-piperazin-l-yl/-4-amino-6,7-dimetoxi- kinazolin, smältpunkt 270oC. Strukturen verifierades genom jäm- förelse med IR-spektrum för föreningen med det av ett autentiskt prov och genom tunnskiktskromatografi på kiselgel med använd- ning av ett 95:5 etylacetatldietylamin-lösningsmedelssystem.Solvent Reaction temperature Reaction time OC hours isobutanol 50 48 1,2-Dimethoxyethane 80 80 diethylene glycol monoethyl ether 200 L (b) 2- [4- (2-furoyl) piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline En solution of 95 mg (0.18 mmol) of 2- [4- (2-furoyl) -piperazin-1-yl] -4-phthalimido-6,7-dimethoxyquinazoline in 2.0 ml of concentrated hydrochloric acid was stirred at room temperature in 2 hours. Then 4.0 ml of chloroform was added and the mixture was adjusted to pH 10 by adding sodium carbonate solution. The chloroform layer was separated and evaporated to dryness to give 55 mg (77.6%) of 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline, m.p. 270 ° C. The structure was verified by comparing the IR spectrum of the compound with that of an authentic sample and by thin layer chromatography on silica gel using a 95: 5 ethyl acetate / diethylamine solvent system.
Exempel 3 4-bensoylamino-2-kloro-6,7-dimetoxikinazolin I en 100 ml trehalsad, rundbottnad kolv, försedd med återflödes- kylare, termometer och torkrör, infördes 32 ml torr tetrahydro- furan, 10 ml torr N,N-dimetylformamid, 6,48 g (0,025 mol) 2,4- dikloro-6,7-dimetoxikinazolin /framställd enligt Curd et al., J. Chem. Soc., 1759 (1948)/, 3,03 g (0,025 mol) bensamid och *J 2,4 g (0,050 mol) 50%-ig (vikt/vikt) natriumhydrid, varvid hydriden tillsattes sist. Den erhållna blandningen upphettades vid âterflöde i 24 timmar, kyldes till rumstemperatur och filtrerades, tvättades med tètrahydrofuran, varvid erhölls 6,0 g (66 %) av natriumsaltet av titelföreningen, smältpunkt 31s°c.Example 3 4-Benzoylamino-2-chloro-6,7-dimethoxyquinazoline In a 100 ml three-necked, round bottom flask equipped with a reflux condenser, thermometer and drying tube, 32 ml of dry tetrahydrofuran, 10 ml of dry N, N-dimethylformamide were introduced. , 6.48 g (0.025 mol) of 2,4-dichloro-6,7-dimethoxyquinazoline / prepared according to Curd et al., J. Chem. Soc., 1759 (1948) /, 3.03 g (0.025 mol) of benzamide and * J 2.4 g (0.050 mol) of 50% (w / w) sodium hydride, the hydride being added last. The resulting mixture was heated at reflux for 24 hours, cooled to room temperature and filtered, washed with tetrahydrofuran to give 6.0 g (66%) of the sodium salt of the title compound, mp 31 ° C.
Efter uppslamning av l,O g av natriumsaltet i 20 ml vatten, surgöring till pH 3-4 med 2N klorvätesyra, omröring i 15 minuter vid 20-25°C, filtrering och torkning över natten erhölls 0,67 g av titelföreningen, smältpunkt 235-24000, Efter om- kristallisation ur isoamylalkohol smälte produkten vid 236-23800.After slurrying 1.0 g of the sodium salt in 20 ml of water, acidifying to pH 3-4 with 2N hydrochloric acid, stirring for 15 minutes at 20-25 ° C, filtration and drying overnight, 0.67 g of the title compound were obtained, m.p. 235 After recrystallization from isoamyl alcohol, the product melted at 236-23800.
Masspektrum uppvisade toppar vid M/e 342 och 344.Mass spectrum showed peaks at M / e 342 and 344.
Exempel 4 4-acetylamino-2-kloro-6,7-dimetoxikinazolin I ett 100 ml reaktionskärl infördes 6,48 g (0,025 mol) 2,4- dikloro-6,7-dimetoxikinazolin, 1,5 g (0,025 mol) acetamid, 32 ml torr N,N-dimetylformamid och 2,4 g (0,050 mol) 50%-ig natriumhydrid. Efter värmning till 40°C började en exoterm reaktion och temperaturen steg hastigt till l20°C under avse- värd skumning. Under denna exoterma period blev reaktionsbland- ningen purpurröd, därefter röd. Blandningen kyldes till 90°C och hölls vid denna temperatur i 2 timmar. Blandningen kyldes därefter till rumstemperatur, uthälldes i l50 ml vatten, tvätta- des med två 100 ml-portioner kloroform och den vattenhaltiga fasen inställdes på pH 2 genom tillsats av koncentrerad klor- vätesyra. Den fällda produkten tillvaratogs genom filtrering och torkades för erhâllning av 86 % utbyte av titelföreningen, smältpunkt 275°C. Endast en fläck erhölls vid tunnskiktskromato- grafi på kiselgel och eluering med 95:5 etylacetat/dietylamin.Example 4 4-Acetylamino-2-chloro-6,7-dimethoxyquinazoline 6.48 g (0.025 mol) of 2,4-dichloro-6,7-dimethoxyquinazoline, 1.5 g (0.025 mol) of acetamide were introduced into a 100 ml reaction vessel. , 32 ml of dry N, N-dimethylformamide and 2.4 g (0.050 mol) of 50% sodium hydride. After heating to 40 ° C, an exothermic reaction began and the temperature rose rapidly to 120 ° C with considerable foaming. During this exothermic period, the reaction mixture turned purple, then red. The mixture was cooled to 90 ° C and kept at this temperature for 2 hours. The mixture was then cooled to room temperature, poured into 150 ml of water, washed with two 100 ml portions of chloroform and the aqueous phase was adjusted to pH 2 by the addition of concentrated hydrochloric acid. The precipitated product was collected by filtration and dried to give 86% yield of the title compound, m.p. 275 ° C. Only one spot was obtained by thin layer chromatography on silica gel eluting with 95: 5 ethyl acetate / diethylamine.
Masspektrum visade en molekylär jon vid M/e 281.Mass spectrum showed a molecular ion at M / e 281.
Exempel 5 4-etoxikarbonylamino-2-kloro-6,7-dimetoxikinazolin 2,4-dikloro-6,7-dimetoxikinazolin (6,48 g, 0,025 mol), 32 ml tetrahydrofuran, etylkarbamat (2,23 g, 0,025 mol) och 50%-ig natriumhydrid (2,4 g, 0,050 mol) infördes i en l00 ml-reaktions-^ kolv försedd med termometer, áterflödeskylare och torkrör. Reak- tionsblandningen återflödeskokades i 2 timmar, varefter 70 ml meta- nol tillsattes långsamt, den resulterande blandningen upphetta- des till 6000 och filtrerades i hett tillstånd. Filtratet koncen- trerades till en tjock uppslamning, den fasta substansen till- varatogs genom filtrering, tvättades med 5 ml kloroform för erhâllning av 5,4 g (70 %) av titelföreningen. Efter omkristalli- < sation ur en blandning av tetrahydrofuran och hexan (2:3) smälte ett prov via 212%.Example 5 4-Ethoxycarbonylamino-2-chloro-6,7-dimethoxyquinazoline 2,4-Dichloro-6,7-dimethoxyquinazoline (6.48 g, 0.025 mol), 32 ml tetrahydrofuran, ethyl carbamate (2.23 g, 0.025 mol) and 50% sodium hydride (2.4 g, 0.050 mol) was introduced into a 100 ml reaction flask equipped with a thermometer, reflux condenser and drying tube. The reaction mixture was refluxed for 2 hours, then 70 ml of methanol was added slowly, the resulting mixture was heated to 6000 and filtered hot. The filtrate was concentrated to a thick slurry, the solid was collected by filtration, washed with 5 ml of chloroform to give 5.4 g (70%) of the title compound. After recrystallization from a mixture of tetrahydrofuran and hexane (2: 3), a sample melted via 212%.
Analys: beräknat för Cl3Hl4N3 O4Cl C 50,09 H 4,53 N 13,48 % Funnet: C 49,95 H 4,46 N 13,54 % Exemgel 6 2-/4-(2-furoy1)-piperazin-l-yl/-4-amino-6,7-dimetoxikinazolin En 50 ml kolv försedd med omrörare, återflödeskylare och torkrör försattes med 160 mg (O,66 mmol) 4-bensoylamino-2-kloro-6,7-di- metoxikinazolin framställd enligt exempel 3, 244,2 mg (l,32 mmol) l-(2-furoyl)-piperazin och 4 ml isoamylalkohol. Den erhållna blandningen upphettades vid 10000 i 4 timmar och kyldes därefter till rumstempertur. Don fällda fasta substansen tillvaratogs genom filtrering och torkades för erhâllning av 60 mg rå pro- dukt. Denna identifierades såsom 2-/4-(2-furoyl)-piperazin-l-yl/- -4-amino-6,7-dimetoxikinazolin genom tunnskiktskiselgelkromato- grafi (etylacetat/dietylamin, 90:10). Det råa materialet renades på en 12,5 x 225 mm kolonn av kiselgel, eluering med bensenlace- ton/myrsyra/vatten (l00:l0O;20:5, beräknat på volymen) för erhâllning av 35 mg, smältpunkt 27500.Analysis: Calculated for Cl -yl / -4-amino-6,7-dimethoxyquinazoline A 50 ml flask equipped with a stirrer, reflux condenser and drying tube was charged with 160 mg (0.66 mmol) of 4-benzoylamino-2-chloro-6,7-dimethoxyquinazoline prepared. according to Example 3, 244.2 mg (1.32 mmol) of 1- (2-furoyl) -piperazine and 4 ml of isoamyl alcohol. The resulting mixture was heated at 10,000 for 4 hours and then cooled to room temperature. The precipitated solid was collected by filtration and dried to give 60 mg of crude product. This was identified as 2- [4- (2-furoyl) -piperazin-1-yl] -4-amino-6,7-dimethoxyquinazoline by thin layer silica gel chromatography (ethyl acetate / diethylamine, 90:10). The crude material was purified on a 12.5 x 225 mm silica gel column, eluting with benzyl acetone / formic acid / water (100: 10 10; 20: 5 by volume) to give 35 mg, mp 27500.
När förfarandet ovan upprepades men med användning av det an- givna lösningsmedlet istället för isoamylalkohol och utförande av reaktionen med användning av den i tabellen nedan angivna temperaturen och tiden i vardera fallet erhölls titelföreningen på liknande sätt.When the above procedure was repeated but using the indicated solvent instead of isoamyl alcohol and carrying out the reaction using the temperature and time given in the table below in each case, the title compound was obtained in a similar manner.
Lösningsmedel Reaktionstemp. OC Reaktionstid, timmar 2-butånol 50 50 2-metoxietanol 80 18 2-metyl-2-pentanol l3O 4 2 dietylenglykol 200 0,25 W v 120 _r~ (51 CD Exemgel 7 2-/4-(2-furoyl)-piperazin-l-yl/-4-amino-6,7-dimetoxikinazolin 4-etoxikarbonylamino-2-kloro-6,7-dimetoxikinazolin (2,0 g, 0,0064 mol) och 23 ml isoamylalkohol infördes i en reaktions- kolv. En lösning av l-(2-furoyl)-piperazin (2,54 g, 0,014 mol) i 18 ml isoamylalkohol tillsattes och blandningen upp- hettades vid l30°C i 4 timmar. De fällda fasta substanserna tillvaratogs i en filtrertratt, tvättades med isoamylalkohol och omrördes därefter med 100 ml 10%-ig vattenlösning av natriumhydroxid. En lika volym kloroform tillsattes och bland- ningen omrördes i 15 minuter. Det organiska skiktet separera- des, koncentrerades till ungefär 25 ml och 50 ml tetrahydro- furan tillsattes. De fasta substanserna tillvaratogs genom filtrering och renades ytterligare genom kromatografi på en kiselgelkolonn (25 X 450 mm), varvid först eluerades med etylacetat och därefter med metanol. Fraktionerna innehållande titelföreningen kombinerades och indunstades till torrhet. Återstoden upptogs i l0 ml kloroform, hexan tillsattes till slöjpunkten, varefter omrördes 15 minuter och kristallerna tillvaratogs genom filtrering, smältpunkt 265°C, utbyte 900 mg (37 %).Solvent Reaction temp. OC Reaction time, hours 2-butanol 50 50 2-methoxyethanol 80 18 2-methyl-2-pentanol 13 4 4 diethylene glycol 200 0.25 W v 120 _r ~ (51 CD Example 7 2- / 4- (2-furoyl) - piperazin-1-yl / -4-amino-6,7-dimethoxykinazoline 4-ethoxycarbonylamino-2-chloro-6,7-dimethoxykinazoline (2.0 g, 0.0064 mol) and 23 ml of isoamyl alcohol were introduced into a reaction flask A solution of 1- (2-furoyl) -piperazine (2.54 g, 0.014 mol) in 18 ml of isoamyl alcohol was added and the mixture was heated at 130 DEG C. for 4 hours. The precipitated solids were collected in a filter funnel, washed with isoamyl alcohol and then stirred with 100 ml of 10% aqueous sodium hydroxide solution, an equal volume of chloroform was added and the mixture was stirred for 15 minutes, the organic layer was separated, concentrated to about 25 ml and 50 ml of tetrahydrofuran were added. The solids were collected by filtration and further purified by chromatography on a silica gel column (25 X 450 mm), eluting first with ethyl acetate and then after with methanol. The fractions containing the title compound were combined and evaporated to dryness. The residue was taken up in 10 ml of chloroform, hexane was added to the flash point, then stirred for 15 minutes and the crystals were collected by filtration, m.p. 265 ° C, yield 900 mg (37%).
När reaktionen ovan upprepades vid BOOC i 18 timmar erhölls ett liknande resultat.When the above reaction was repeated at BOOC for 18 hours, a similar result was obtained.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69620176A | 1976-06-15 | 1976-06-15 |
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| SE450120B true SE450120B (en) | 1987-06-09 |
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| Application Number | Title | Priority Date | Filing Date |
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| SE7705745A SE435380B (en) | 1976-06-15 | 1977-05-16 | PROCEDURE FOR THE PREPARATION OF CHINAZOLINE COMPOUNDS |
| SE8107554A SE450120B (en) | 1976-06-15 | 1981-12-16 | NEW DIMETOXICINAZOLINE DERIVATIVES TO USE FOR PREPARATION OF 2 (4-SUBSTITUTED PIPERAZIN-1-YL) -4-AMINO-6,7-DIMETOXICINAZOLINES |
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| BG (3) | BG35748A3 (en) |
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| EG (1) | EG12922A (en) |
| ES (1) | ES459364A1 (en) |
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| DE3346675A1 (en) * | 1983-12-23 | 1985-07-04 | Beiersdorf Ag, 2000 Hamburg | SUBSTITUTED 1- (4-AMINO-6,7-DIALKOXY-CHINAZOLINYL) -4- CYCLOHEXENYL DERIVATIVES OF PIPERAZINE AND HOMOPIPERAZINE, METHODS FOR THE PRODUCTION THEREOF, AND THEIR USE, AND ITS RELATED PRODUCTS |
| AT384218B (en) * | 1985-12-04 | 1987-10-12 | Gerot Pharmazeutika | METHOD FOR PRODUCING NEW CHINAZOLINE DERIVATIVES |
| CA2077252C (en) * | 1992-08-31 | 2001-04-10 | Khashayar Karimian | Methods of making ureas and guanidines, and intermediates therefor |
| US5679683A (en) * | 1994-01-25 | 1997-10-21 | Warner-Lambert Company | Tricyclic compounds capable of inhibiting tyrosine kinases of the epidermal growth factor receptor family |
| IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
| IL112248A0 (en) | 1994-01-25 | 1995-03-30 | Warner Lambert Co | Tricyclic heteroaromatic compounds and pharmaceutical compositions containing them |
| US5932538A (en) * | 1996-02-02 | 1999-08-03 | Nitromed, Inc. | Nitrosated and nitrosylated α-adrenergic receptor antagonist compounds, compositions and their uses |
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| US3511836A (en) | 1967-12-13 | 1970-05-12 | Pfizer & Co C | 2,4,6,7-tetra substituted quinazolines |
| US3669968A (en) | 1970-05-21 | 1972-06-13 | Pfizer | Trialkoxy quinazolines |
| JPS536156B2 (en) * | 1972-10-30 | 1978-03-04 | ||
| US3935213A (en) | 1973-12-05 | 1976-01-27 | Pfizer Inc. | Process for hypotensive 4-amino-2-(piperazin-1-yl) quinazoline derivatives |
| JPS50126682A (en) * | 1974-03-25 | 1975-10-04 |
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