SE449747B - PROCEDURE FOR PREPARING N- / 2 - // 5 - / (DIMETHYLAMINO) METHYL / -2-FURANYLMETHYL / -TIO / ETHYL / N'-METHYL-2-NITRO-1,1-ETHENYAMINE (RANITIDINE) - Google Patents
PROCEDURE FOR PREPARING N- / 2 - // 5 - / (DIMETHYLAMINO) METHYL / -2-FURANYLMETHYL / -TIO / ETHYL / N'-METHYL-2-NITRO-1,1-ETHENYAMINE (RANITIDINE)Info
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- SE449747B SE449747B SE8100074A SE8100074A SE449747B SE 449747 B SE449747 B SE 449747B SE 8100074 A SE8100074 A SE 8100074A SE 8100074 A SE8100074 A SE 8100074A SE 449747 B SE449747 B SE 449747B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
- C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no 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 the ring nitrogen atom
- C07D203/12—Radicals substituted by nitrogen atoms not forming part of a nitro radical
Description
449 747 2 t.ex. inom intervallet 10-BOOC. Reaktionen genomföras företrädes- vis i en inert atmosfär, t.ex. i kvävgasatmosfär. Enligt en mo- difikation av förfarandet kan tiolen med formel II omsättas med alkyleringsmedlet med formel III i ett tvåfassystem, t.ex. i klo- roform och vatten, i närvaro av en fasöverföríngskatalysator (t.ex. ett kvaternärt ammoniumsalt, såsom bensyltrietylammonium- klorid) och en bas (t.ex. natriumhydroxid). 449 747 2 e.g. within the range of 10-BOOC. The reaction is preferably carried out in an inert atmosphere, e.g. in a nitrogen atmosphere. According to a modification of the process, the thiol of formula II can be reacted with the alkylating agent of formula III in a two phase system, e.g. in chloroform and water, in the presence of a phase transfer catalyst (eg a quaternary ammonium salt such as benzyltriethylammonium chloride) and a base (eg sodium hydroxide).
Särskilt fördelaktiga betingelser för genomförande av alkyle- ringsreaktionen är behandling av tiolen med formel II med alkyle- ringsmedlet med formel III (där R1 betecknar gruppen -CH2CH2Cl och R2 betecknar en väteatom) antingen i närvaro av en alkalimetall- hydroxid (t.ex. kaliumhydroxid) i vatten, eller i närvaro av ka- liumkarbonat med användning av vattenhaltig tetrahydrofuran såsom lösningsmedel. Reaktionen genomföras lämpligen vid rumstemperatur i kvävgasatmosfär.Particularly advantageous conditions for carrying out the alkylation reaction are the treatment of the thiol of formula II with the alkylating agent of formula III (where R 1 represents the group -CH 2 CH 2 Cl and R 2 represents a hydrogen atom) either in the presence of an alkali metal hydroxide (eg potassium hydroxide ) in water, or in the presence of potassium carbonate using aqueous tetrahydrofuran as solvent. The reaction is conveniently carried out at room temperature in a nitrogen atmosphere.
När symbolerna R1 och R2 bildar en etylenimincgrupp tillsam- mans med den kväveatom, till vilken de är bundna, kan reaktionen genomföras antingen i frånvaro av lösningsmedel eller i närvaro av ett lösningsmedel. Såsom exempel på lämpliga lösningsmedel kan man nämna vatten, en alkanol (t.ex. metanol) och dimetylformamid.When the symbols R1 and R2 form an ethyleneimine group together with the nitrogen atom to which they are attached, the reaction can be carried out either in the absence of solvent or in the presence of a solvent. Examples of suitable solvents are water, an alkanol (eg methanol) and dimethylformamide.
Reaktionen genomföres företrädesvis under upphettning, t.ex. vid 100OC, och i en inert atmosfär, t.ex. i kvävgasatmosfär.The reaction is preferably carried out under heating, e.g. at 100 ° C, and in an inert atmosphere, e.g. in a nitrogen atmosphere.
Tiolen med formel II kan användas direkt, eller den kan alst- ras in situ utgående från ett syraadditionssalt, såsom ett oxalat- salt. När reaktionen genomföres i närvaro av en bas, kan man al- ternativt framställa tiolen med formel II in situ utgående från en isotiokarbamid med formeln NH e _ n Mezwcnz /' *~«Cn SCNH (IV) 0 2 2 eller ett salt därav, t.ex. ett bis-maleatsalt, under de basiska reaktionsbetingelserna. .The thiol of formula II can be used directly, or it can be generated in situ starting from an acid addition salt, such as an oxalate salt. Alternatively, when the reaction is carried out in the presence of a base, the thiol of formula II may be prepared in situ starting from an isothiourea of the formula NH or a Mezwcnz /'n cn SCNH (IV) 0 2 2 or a salt thereof. for example a bis-maleate salt, under the basic reaction conditions. .
Tiolen med formel II kan framställas genom att motsvarande alkohol med formeln -*'“/ÉâïÉš“““““cu ms (V) neznçu 2 2 0 449 747 3 i omsättes med tiokarbamid i närvaro av en koncentrerad syra, såsom koncentrerad saltsyra._ Härvid bildas isotiokarbamiden med formel IV, vilken sedan omvandlas till tiolen med formel II genom behand- ling med en bas, såsom natriumkarbonat eller 5N natriumhydroxid, företrädesvis i närvaro av en antioxidant, såsom natriumditionit eller natriummetabisulfit. När den sålunda bildade fria basen väl har isolerats, kan den omvandlas till ett stabilt syraadditions- salt genom behandling med en lämplig syra, särskilt oxalsyra, före- trädesvis i ett lösningsmedel, såsom tetrahydrofuran.The thiol of formula II can be prepared by reacting the corresponding alcohol of formula (c) with thiourea in the presence of a concentrated acid, such as concentrated hydrochloric acid. This forms the isothiourea of formula IV, which is then converted to the thiol of formula II by treatment with a base such as sodium carbonate or 5N sodium hydroxide, preferably in the presence of an antioxidant such as sodium dithionite or sodium metabisulfite. Once the free base thus formed has been isolated, it can be converted into a stable acid addition salt by treatment with a suitable acid, especially oxalic acid, preferably in a solvent such as tetrahydrofuran.
Om man önskar isolera ísotiokarbamiden med formel IV, isoleras även denna företrädesvis i form av ett stabilt salt, t.ex. bis- maleatet, genom att den behandlas med en lämplig syra, företrädes- vis i ett lösningsmedel, såsom tetrahydrofuran.If it is desired to isolate the isothiourea of formula IV, it is also preferably isolated in the form of a stable salt, e.g. the bis-maleate, by treating it with a suitable acid, preferably in a solvent such as tetrahydrofuran.
Den förening med formel III, där R1 betecknar gruppen -CH2CH2L, där L betecknar en halogenatom (t.ex. klor), och R2 betecknar en väteatom, kan framställas genom att en förening med formeln HHNOZ Iflcnnme ' (vi) där L' betecknar en avspjälkbar grupp, t.ex. en metyltiogrupp, om- sättes med en haloalkylamin, såsom kloretylamin, företrädesvis i form av ett salt, t.ex. hydrokloriden. Reaktionen genomföras i ett lämpligt lösningsmedel, såsom vatten, i närvaro av en bas, så- som trietylamin, och företrädesvis vid en förhöjd temperatur, t. ex. vid ca 10000.The compound of formula III, wherein R 1 represents the group -CH 2 CH 2 L, where L represents a halogen atom (eg chlorine), and R 2 represents a hydrogen atom, can be prepared by a compound of the formula HHNO 2 I fl cnnme '(vi) where L' represents a cleavable group, e.g. a methylthio group, is reacted with a haloalkylamine, such as chloroethylamine, preferably in the form of a salt, e.g. the hydrochlorides. The reaction is carried out in a suitable solvent, such as water, in the presence of a base, such as triethylamine, and preferably at an elevated temperature, e.g. at about 10000.
Den förening med formel III, där R1R2N betecknar en etylen- iminogrupp, kan framställas genom att etylenimin omsättes med en nitroetenamin med formeln CHNO H2 L" ~ CNHMG (VII) där L" betecknar en avspjälkbar grupp, t.ex. en Ci-C4-alkoxigrupp eller en Cl-Cu-alkyltiogrupp, företrädesvis metyltio. Reaktionen kan genomföras i ett lämpligt aprotiskt lösningsmedel, såsom ace- tonitril._ Syraadditionssalterna av tiolen med formel II, den före- ning med formel III, där R1R N betecknar en etyleniminogrupp, dvs. 2 föreningen med formeln 449 7471 CH CUNOZ 2 \N-CNHM<= (VIII) cnz , 'W samt isotiokarbamiden med formel IV och syradditionssalter därav är alla nya föreningar som omfattas av föreliggande uppfinning.The compound of formula III, wherein R 1 R 2 N represents an ethyleneimino group, can be prepared by reacting ethylenimine with a nitroethenamine of the formula CHNO H 2 L "-CNHMG (VII) where L" represents a leaving group, e.g. a C 1 -C 4 alkoxy group or a C 1 -C 6 alkylthio group, preferably methylthio. The reaction can be carried out in a suitable aprotic solvent, such as acetonitrile. The acid addition salts of the thiol of formula II, the compound of formula III, wherein R1R N represents an ethyleneimino group, i.e. The compound of the formula 449 7471 CH CUNOZ 2 \ N-CNHM <= (VIII) cnz, W and the isothiourea of the formula IV and acid addition salts thereof are all novel compounds encompassed by the present invention.
Tiolen med formel II och isotiokarbamiden med formel IV är icke särskilt stabila, men man har funnit, att de kan stabiliseras genom att de omvandlas till syraadditionssalter. Såsom exempel på dylika stabila syraadditionssalter kan man nämna hydroklorider, sul- fater, alkyl- och arylsulfonater, acetater, fumarater, maleater och bensoater. Ett föredraget syraadditionssalt av tíolen med formel II är oxalatet, och ett föredraget syraadditionssalt av isotiokarb- amiden med formel IV är bis-maleatet.The thiol of formula II and the isothiourea of formula IV are not very stable, but it has been found that they can be stabilized by converting them to acid addition salts. Examples of such stable acid addition salts are hydrochlorides, sulfates, alkyl and aryl sulfonates, acetates, fumarates, maleates and benzoates. A preferred acid addition salt of the thiol of formula II is the oxalate, and a preferred acid addition salt of the isothiourea of formula IV is the bis-maleate.
Uppfinningen illustreras genom följande exempel. Exemplen1%E illustrerar framställning av utgängsprodukter och.mellanprodukter, och exemplen 1-5 illustrerar framställning av slutprodukten. I Exempel A. 1-[TIS-[Ydimetylamino)metyl]-2-furanyl]metyl]-tio]- metanimidamid-maleat (1:2. 5,1 g 5-¿Ydimetylamino)metyl?-2-furanmetanol sattes undan för undan till en lösning av 1,53 g tiokarbamid i-5 ml koncentrerad saltsyra. Sedan lösningen fått stå vid rumstemperatur under 18 tim- mar upphettades den vid 98-10000 under 30 minuter. Lösningen kyl- des därefter, 100 ml tetrahydrofuran och ett överskott av vatten- fritt natriumkarbonat tillsattes, och efter 30 minuter filtrerades blandningen. Till filtratet sattes en lösning av H,65 g maleinsyra i H0 ml torr tetrahydrofuran, och det bildade fasta ämnet avfiltre- rades och tvättades med tetrahydrofuran och eter. Härvid erhölls 8,1 g av titelföreningen med en smältpunkt av 144-1Ä50C.The invention is illustrated by the following examples. Examples 1% E illustrate the preparation of starting and intermediate products, and Examples 1-5 illustrate the preparation of the final product. In Example A. 1- [TIS- [Dimethylamino) methyl] -2-furanyl] methyl] thio] -methanimidamide maleate (1: 2. 5.1 g of 5-dimethylamino) methyl? -2-furanmethanol was omitted. precede to a solution of 1.53 g of thiourea in 5 ml of concentrated hydrochloric acid. After allowing the solution to stand at room temperature for 18 hours, it was heated at 98-10000 for 30 minutes. The solution was then cooled, 100 ml of tetrahydrofuran and an excess of anhydrous sodium carbonate were added, and after 30 minutes the mixture was filtered. To the filtrate was added a solution of H, 65 g maleic acid in H0 ml dry tetrahydrofuran, and the solid formed was filtered off and washed with tetrahydrofuran and ether. This gave 8.1 g of the title compound, m.p. 144 DEG-150 DEG.
Exempel B. 5-[(dimetylamino)metyL7-2-furanmetantiol-okalat (1:1). ' 7 7,76 g 5-[Tdimetylamino)metyl]-2-furanmetanol sattes undan för undan till en lösning av 3,81 g tiokarbamid i 12,5 ml koncentrerad saltsyra. Efter 18 timmar upphettades lösningen vid 98-10000 un- der 30 minuter, varpå den indunstades till en liten volym. En lös- : ning av 10 g natriumhydroxid i 50 ml vatten och 10 g natriumditio- nit tillsattes, och efter 2 timme extraherades lösningen med eter (6 x 50 ml). Till vattenfasen sattes 35 g borsyra, och den erhåll- 449 747 5 na suspensionen extraherades med eter (4 x 50 ml). Till de före- nade eterextrakten sattes 2 g natriumditionit och överskott av vat- tenfritt natriumkarbonat. Efter 3 timmar filtrerades blandningen ned i en lösning av 6,5 g oxalsyra i 60 ml torr tetrahydrofuran.Example B. 5 - [(dimethylamino) methyl] -2-furanmethanethiol okalate (1: 1). 7.76 g of 5- [Dimethylamino) methyl] -2-furanmethanol were gradually added to a solution of 3.81 g of thiourea in 12.5 ml of concentrated hydrochloric acid. After 18 hours, the solution was heated at 98-10000 for 30 minutes, after which it was evaporated to a small volume. A solution of 10 g of sodium hydroxide in 50 ml of water and 10 g of sodium dithionite was added, and after 2 hours the solution was extracted with ether (6 x 50 ml). To the aqueous phase was added 35 g of boric acid, and the resulting suspension was extracted with ether (4 x 50 ml). To the combined ether extracts were added 2 g of sodium dithionite and excess anhydrous sodium carbonate. After 3 hours, the mixture was filtered into a solution of 6.5 g of oxalic acid in 60 ml of dry tetrahydrofuran.
Det bildade fasta ämnet avfiltrerades, tvättades med tetrahydrofuran och torkades. Härvid erhölls 5,84 g av titelföreningen med en smältpunkt av 116,5-11800.The solid formed was filtered off, washed with tetrahydrofuran and dried. This gave 5.84 g of the title compound, m.p. 116.5-11800.
Exempel C. N-(2-kloretyl)-N'-metyl-2-nitro-1,1-etendiamin.Example C. N- (2-chloroethyl) -N'-methyl-2-nitro-1,1-ethenediamine.
Till en lösning av 5,95 g N-metyl-(1-metyltio)-2-nitroetenamin och 18,56 g 2-kloretanamin-hydroklorid i 4 ml vatten sattes 24 ml trietylamin vid 98-10000. Reaktionsblandningen omrördes vid 98- 10000 under 10 minuter, varpå den sattes under vakuum (12-20 mm Hg) under 50 minuter. Därefter tillsattes 8~ml vatten, och den re- sulterande blandningen upphettades i vakuum vid 98-100°C under 20 minuter. Till återstoden sattes 200 ml aceton och ett överskott av vattenfritt magnesiumsulfat, och den resulterande suspensionen koka- des under återflöde i 45 minuter. Det bildade fasta ämnet avfiltre- rades och tvättades med varm aceton (3 x 50 ml). Filtratet före- nades med tvättlösningarna, och den härvid erhållna blandningen kyldes. Den resulterande kristallina fällningen avskildes genom filtrering. Filtratet koncentrerades till en volym av 100 ml, och det bildade fasta ämnet avfiltrerades. Filtratet indunstades till en liten volym och kromatograferades på kiseldioxid med användning av aceton såsom elueringsmedel. Det lämpliga eluatet indunstades i vakuum, och återstoden suspenderades i en blandning av etylacetat och eter i volymförhållandet 1:4. Suspensionen filtrerades, var- vid man erhöll 2,8 g av titelföreningen med en smältpunkt av 115- 115°c.To a solution of 5.95 g of N-methyl- (1-methylthio) -2-nitroethenamine and 18.56 g of 2-chloroethanamine hydrochloride in 4 ml of water was added 24 ml of triethylamine at 98-10000. The reaction mixture was stirred at 98-10,000 for 10 minutes, then placed under vacuum (12-20 mm Hg) for 50 minutes. Then 8 ml of water was added, and the resulting mixture was heated in vacuo at 98-100 ° C for 20 minutes. To the residue were added 200 ml of acetone and an excess of anhydrous magnesium sulfate, and the resulting suspension was refluxed for 45 minutes. The solid formed was filtered off and washed with hot acetone (3 x 50 ml). The filtrate was combined with the washing solutions, and the resulting mixture was cooled. The resulting crystalline precipitate was separated by filtration. The filtrate was concentrated to a volume of 100 ml, and the solid formed was filtered off. The filtrate was evaporated to a small volume and chromatographed on silica using acetone as eluent. The appropriate eluate was evaporated in vacuo, and the residue was suspended in a mixture of ethyl acetate and ether in a volume ratio of 1: 4. The suspension was filtered to give 2.8 g of the title compound, m.p. 115-115 ° C.
Produkten gav ett Rf-värde av 0,4 vid tunnskiktskromatografi på silikagel med användning av 2-butanon såsom elueringsmedel.The product gave an Rf value of 0.4 by thin layer chromatography on silica gel using 2-butanone as eluent.
Exempel D. N-metyl-Q-(nitrometylen)-1-aziridinmetanamin.Example D. N-methyl-Q- (nitromethylene) -1-aziridinemethanamine.
En lösning av 0,47 g etylenimin och 1,48 g N-metyl-(1-metyl- tio)-2-nitroetenamin i 5 ml acetonitril omrördes vid rumstemperatur under 2 dygn. Den resulterande suspensionen indunstades i vakuum vid rumstemperatur, och återstoden extraherades med 100 ml varmt etylacetat. Extraktet_indunstades i vakuum, och återstoden sus- penderades i 50 ml etylacetat, varpå den resulterande suspensionen filtrerades. Filtratet indunstades till en volym av ca 5 ml och_ kromatograferades på kiseldioxid med användning av dietylacetat såsom elueringsmedel. Man indunstade i vakuum det eluat, vilket 449 747 _ 6 gav ett Rf-värde av 0,28 vid tunnskiktskromatografi på kiseldioxid med användning av etylacetat såsom elueringsmedel. Härvid erhölls 0,33 g av titelföreningen med en smältpunkt av 118-11900.A solution of 0.47 g of ethyleneimine and 1.48 g of N-methyl- (1-methylthio) -2-nitroethenamine in 5 ml of acetonitrile was stirred at room temperature for 2 days. The resulting suspension was evaporated in vacuo at room temperature, and the residue was extracted with 100 ml of hot ethyl acetate. The extract was evaporated in vacuo and the residue was suspended in 50 ml of ethyl acetate, after which the resulting suspension was filtered. The filtrate was evaporated to a volume of about 5 ml and chromatographed on silica using diethyl acetate as eluent. The eluate was evaporated in vacuo to give an Rf value of 0.28 by thin layer chromatography on silica using ethyl acetate as eluent. This gave 0.33 g of the title compound, m.p. 118-11900.
Exempel E. 5-[Tdimetylamino)metyl]-2-furanmetantiol-oxalat (lzl).Example E. 5- [Dimethylamino) methyl] -2-furanmethanethiol oxalate (IIz).
En blandning av 83,5 g kaliumkarbonat, 22,9 g natriummetabisul- fit och 26,73 g 1-[2¶5-[(dimetylamino)metyl]-2-furanyl]metyl]-tiq7- metanímidamid-maleat (1:2) i 140 ml vatten och 160 ml eter omrördes i kvävgasatmosfär vid rumstemperatur under 24 timmar. Därefter tillsattes 10 g vattenfritt natriumkarbonat, och efter omrörning un- der ytterligare 2 timmar avskildes eterfasen och tvättades med en lösning av 5 g natriummetabisulfit och 8 g kaliumkarbonat i 60 ml vatten. Efterextraktet torkades över natriumsulfat under 1 timme och filtrerades därpå ned i en lösning av 7,6 g oxalsyra i 100 ml tetrahydrofuran. Härvid erhölls 13,33 g av ett fast ämne, vilket avskíldes och kristalliserades i tetrahydrofuran. Man erhöll här- vid 12,20 av titelföreningen med en smältpunkt av 116,5-11900.A mixture of 83.5 g of potassium carbonate, 22.9 g of sodium metabisulphite and 26.73 g of 1- [2,5 - [(dimethylamino) methyl] -2-furanyl] methyl] -tiq7-methanimidamide maleate (1: 2) in 140 ml of water and 160 ml of ether were stirred in a nitrogen atmosphere at room temperature for 24 hours. Then 10 g of anhydrous sodium carbonate were added, and after stirring for a further 2 hours, the ether phase was separated and washed with a solution of 5 g of sodium metabisulfite and 8 g of potassium carbonate in 60 ml of water. The after-extract was dried over sodium sulfate for 1 hour and then filtered into a solution of 7.6 g of oxalic acid in 100 ml of tetrahydrofuran. This gave 13.33 g of a solid, which was separated and crystallized from tetrahydrofuran. This gave 12.20 of the title compound, m.p. 116.5-11900.
Exempel 1. N-[2-[Z5-[(dimetylamino)metyl7-2-furanylmetyl]- tiqjetyl]-N'-metyl-2-nitro-1,1-etendiamin. ' En blandning av 0,9 g N-(2-kloretyl)-N'-metyl-2-nitro~1,1- etendiamin, 1,3 g 5-[(dimetylamino)metyl]-2-furanmetantiol-oxalat (1:1) och 2,7 g kaliumkarbonat i 10 ml vatten och 10 ml tetrahydro- furan omrördes i kvävgasatmosfär vid rumstemperatur under 5 dygn.Example 1. N- [2- [Z5 - [(dimethylamino) methyl] -2-furanylmethyl] triethyl] -N'-methyl-2-nitro-1,1-ethylenediamine. A mixture of 0.9 g of N- (2-chloroethyl) -N'-methyl-2-nitro-1,1-ethylenediamine, 1.3 g of 5 - [(dimethylamino) methyl] -2-furanmethanethiol oxalate ( 1: 1) and 2.7 g of potassium carbonate in 10 ml of water and 10 ml of tetrahydrofuran were stirred in a nitrogen atmosphere at room temperature for 5 days.
Suspensionen indunstades sedan i vakuum, återstoden blandades med 40 ml vatten, och den resulterande suspensionen extraherades med eter (2 x 30 ml). Vattenfasen indunstades i vakuum, och återstoden indunstades med etanol (2 x 10 ml). Till den resulterande åter- stoden sattes 20 ml tetrahydrofuran, mangnesiumsulfat och avfärg- ningskol, och efter 1 timme filtrerades blandningen. Efter in- dunstning av filtratet erhölls 1 g av en olja, vilken kromatogra- ferudos på kiseldloxid, varvid man såsom elueríngsmedel använde en blandning av metanol och 0,88 ammoniak i volymförhållandet 79:1.The suspension was then evaporated in vacuo, the residue mixed with 40 ml of water, and the resulting suspension extracted with ether (2 x 30 ml). The aqueous phase was evaporated in vacuo and the residue was evaporated with ethanol (2 x 10 ml). To the resulting residue was added 20 ml of tetrahydrofuran, manganese sulfate and decolorizing charcoal, and after 1 hour, the mixture was filtered. After evaporation of the filtrate, 1 g of an oil was obtained, which was chromatographed on silica, using as eluent a mixture of methanol and 0.88 ammonia in a volume ratio of 79: 1.
Det lämpliga eluatet indunstades, och den oljiga återstoden (0,66 g) extraherades med varmt isopropylacetat. Det bildade fasta ämnet avfiltrerades, varvid man erhöll 0,4 g av titelföreningen med en smältpunkt av 65-6800. Ingen smältpunktssänkning erhölls när pro- dukten blandades med ett prov framställt enligt den metod som har beskrivits i exempel 15 i den brittiska patentskriften 1 565 966. 1» 449 747 '7 .The appropriate eluate was evaporated, and the oily residue (0.66 g) was extracted with hot isopropyl acetate. The solid formed was filtered off to give 0.4 g of the title compound, m.p. 65-6800. No melting point decrease was obtained when the product was mixed with a sample prepared according to the method described in Example 15 of British Patent Specification 1,565,966. 1 449 747 '7.
Exempel 2. N-[2-225-[(dimetylamino)metyl]-2-furanylmetyl]- tiq]etyl]-N'-metyl-2-nitro-1,1-etendiamin.Example 2. N- [2-225 - [(dimethylamino) methyl] -2-furanylmethyl] tiq] ethyl] -N'-methyl-2-nitro-1,1-ethenediamine.
En blandning av 2,23 g 1-[II5-[(dimetylamino)metyl]-2-furanyl]- mety1]-tiq]metanimidamid-maleat (1:2), 0,9 g N-(2-kloretyl)-N'- metyl-2-nitro-1,1-etendiamin och 3,H6 g kaliumkarbonat i 10 ml vat- ten och 10 ml tetrahydrofuran omrördes i kvävgasatmosfär vid rums- temperatur under 5 dygn. Suspensionen indunstades därefter i va- kuum. Återstoden suspenderades i 50 ml vatten, och den härvid er- hållna suspensionen extraherades med eter (2 x 40 ml). Vattenfasen indunstades i vakuum, och till återstoden sattes magnesiumsulfat och 100 ml tetrahydrofuran. Efter 18 timmar filtrerades blandningen, och filtratet indunstades till ett halvfast ämne, vilket kromatogra- ferades på kiseldioxid med användning av metanol såsom elueringsme- del. Det lämpliga eluatet indunstades i vakuum, varvid man erhöll 0,5 g av titelföreningen. Produkten hade identiskt samma NMR- spektrum som den i exempel 1 framställda produkten..A mixture of 2.23 g of 1- [II5 - [(dimethylamino) methyl] -2-furanyl] -methyl] -tiq] methanimidamide maleate (1: 2), 0.9 g of N- (2-chloroethyl) - N'-methyl-2-nitro-1,1-ethylenediamine and 3.1 H6 g of potassium carbonate in 10 ml of water and 10 ml of tetrahydrofuran were stirred in a nitrogen atmosphere at room temperature for 5 days. The suspension was then evaporated in vacuo. The residue was suspended in 50 ml of water, and the resulting suspension was extracted with ether (2 x 40 ml). The aqueous phase was evaporated in vacuo, and to the residue were added magnesium sulfate and 100 ml of tetrahydrofuran. After 18 hours, the mixture was filtered, and the filtrate was evaporated to a semi-solid, which was chromatographed on silica using methanol as eluent. The appropriate eluate was evaporated in vacuo to give 0.5 g of the title compound. The product had identically the same NMR spectrum as the product prepared in Example 1.
Exempel 3. N-[2-[X5-Äïdimetylamino)metyl]-2-furanylmetyl]- tiojetylf-N'-metyl-2-nitro-1,1-etendiamin.Example 3. N- [2- [X5-Dimethylamino) methyl] -2-furanylmethyl] -thioethyl-N'-methyl-2-nitro-1,1-ethylenediamine.
Till en blandning av 0,156 g 5-[Ydimetylamino)metyl]-2-furan- metantiol-oxalat (1:1), 0,05 g natriumditionit och 0,15 g vatten- fritt natriumkarbonat i 0,Ä ml vatten sattes 15 ml eter och ett överskott av vattenfritt natriumkarbonat. Den resulterande bland- ningen filtrerades, och filtratet indunstades i vakuum. Till äter- stoden sattes 0,072 g N-metyl-ck-(nitrometylen)-1-aziridinmetan- amin och 2 ml metanol, och den erhållna lösningen indunstades till torrhet.» Äterstoden upphettades vid 98-10000 under 1,25 timmar, och produkten kromatograferades på kiseldioxid, varvid man såsom elueringsmedel använde en blandning av metanol och 0,88 ammoniak i volymförhållandet 79:1. Det lämpliga eluatet indunstades i va- kuum, varvid man erhöll 0,113 g av titelföreningen. Produkten hade identiskt samma NMR-spektrum som de i exemplen 1 och 2 framställda produkterna.To a mixture of 0.156 g of 5- [dimethylamino) methyl] -2-furan-methanethiol oxalate (1: 1), 0.05 g of sodium dithionite and 0.15 g of anhydrous sodium carbonate in 0.1 ml of water was added 15 ml of water. ether and an excess of anhydrous sodium carbonate. The resulting mixture was filtered, and the filtrate was evaporated in vacuo. To the residue was added 0.072 g of N-methyl-ck- (nitromethylene) -1-aziridinemethanamine and 2 ml of methanol, and the resulting solution was evaporated to dryness. The residue was heated at 98 DEG-100 DEG C. for 1.25 hours, and the product was chromatographed on silica using a mixture of methanol and 0.88 ammonia in a volume ratio of 79: 1 as eluent. The appropriate eluate was evaporated in vacuo to give 0.113 g of the title compound. The product had identical NMR spectrum as the products prepared in Examples 1 and 2.
Exempel 4. N-[2-225-Åïdimetylamino)metyl]-2-furanylmetyl]- tio]etvl]-N'-metyl-2-nitro-1,1-etendiamin.Example 4. N- [2-225-β-Dimethylamino) methyl] -2-furanylmethyl] -thio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine.
Till en omrörd blandning av 1,31 g 5-[Kdimetylamino)metyl]-2- furanmetantiol-oxalatw(1f1) och 1,08 g N-(2-kloretyl)-N'-metyl-2- nitro-1,1-etendiamin i 20 ml vatten sattes i kvävgasatmosfär vid en temperatur av H5°C en lösning av 1,0H g kaliumhydroxid i 3 ml vatten. Den resulterande lösningen omrördes vid Ä5oC under 2,5 tim- mar och därefter vid rumstemperatur under 15 timmar. Lösningen in- 449 747 8 dunstades sedan i vakuum, och återstoden löstes i vatten. En luft- -ström leddes genom den erhållna lösningen under 15 minuter. Den resulterande blandningen extraherades med eter (2 x 15 ml), och vattenfasen indunstades i vakuum. Till återstoden sattes 70 ml tetrahydrofuran, ett överskott av vattenfritt natriumkarbonat samt avfärgningskol. Efter 1 timme filtrerades blandningen, och filtra- tet indunstades i vakuum. Den erhållna oljiga återstoden löstes i 8 ml H-metylpentan-2-on. Det bildade fasta ämnet avfiltrerades och tvättades med 4-metylpentan-2-on. Härvid erhölls 0,72 g av titel- föreningen med en smältpunkt av 63-6600. Ingen smältpunktssänkning erhölls när produkten blandades med ett prov framställt enligt den metod som beskrives i exempel 15 i den brittiska patentskriften 1 565 966.To a stirred mixture of 1.31 g of 5- [Dimethylamino) methyl] -2-furanmethanethiol oxalate (1f1) and 1.08 g of N- (2-chloroethyl) -N'-methyl-2-nitro-1,1 -ethenediamine in 20 ml of water was added in a nitrogen atmosphere at a temperature of H5 ° C a solution of 1.0H g of potassium hydroxide in 3 ml of water. The resulting solution was stirred at 50 ° C for 2.5 hours and then at room temperature for 15 hours. The solution was then evaporated in vacuo, and the residue was dissolved in water. An air stream was passed through the resulting solution for 15 minutes. The resulting mixture was extracted with ether (2 x 15 ml), and the aqueous phase was evaporated in vacuo. To the residue were added 70 ml of tetrahydrofuran, an excess of anhydrous sodium carbonate and decolorizing carbon. After 1 hour, the mixture was filtered, and the filtrate was evaporated in vacuo. The resulting oily residue was dissolved in 8 ml of H-methylpentan-2-one. The solid formed was filtered off and washed with 4-methylpentan-2-one. This gave 0.72 g of the title compound, m.p. 63-6600. No melting point drop was obtained when the product was mixed with a sample prepared according to the method described in Example 15 of British Patent Specification 1,565,966.
Exempel 5. N-Å?-¿2B-ÅKdimetylamino)metyI]-2-furanylmetyl]- tiqfetylj-N'-metyl-2-nitro-1,1-etendiamin.Example 5. N-N-(β-β-C (dimethylamino) methyl] -2-furanylmethyl] triethyl-N'-methyl-2-nitro-1,1-ethenediamine.
Till en omrörd lösning av 2,23 g 1-IÄÉ-[Ydimetylamino)metyl]- 2-furanylmetylftiqymetanimidamid-maleat (1:2) och 1,08 g N-(2- kloretyl)-N'-metyl-2-nitro-1,1-etendiamin i 20 ml vatten sattes i kvävgasatmosfär vid en temperatur av ÄBOC en lösning av 1,68 g kaliumhydroxid i 3 ml vatten. Efter 40 timmar vid rumstemperatur extraherades lösningen med eter (2 x 50 ml), varpå vattenfasen in- dunstades i vakuum. Till återstoden sattes 70 ml tetrahydrofuran, avfärgningskol och ett överskott av vattenfritt natríumkarbonat, och den resulterande blandningen kokades under återflöde i 30 mi- nuter. Efter 5 timmar filtrerades blandningen, och filtratet in- dunstades i vakuum till ett halvfast ämne, vilket löstes i en bland- ning av metanol och aceton och kromatograferades på kiseldioxid, varvid man såsom elueringsmedel använde en blandning av lika volym- delar metanol och aceton. Det lämpliga eluatet indunstades i va- kuum, varvid man erhöll 0,37 g av titelföreningen såsom en olja.To a stirred solution of 2.23 g of 1-[1- [Ydimethylamino) methyl] -2-furanylmethylthiphymethanimidamide maleate (1: 2) and 1.08 g of N- (2-chloroethyl) -N'-methyl-2-nitro -1,1-Ethenediamine in 20 ml of water was added in a nitrogen atmosphere at a temperature of ÄBOC a solution of 1.68 g of potassium hydroxide in 3 ml of water. After 40 hours at room temperature, the solution was extracted with ether (2 x 50 ml) and the aqueous phase was evaporated in vacuo. To the residue were added 70 ml of tetrahydrofuran, decolorizing carbon and an excess of anhydrous sodium carbonate, and the resulting mixture was refluxed for 30 minutes. After 5 hours, the mixture was filtered, and the filtrate was evaporated in vacuo to a semi-solid, which was dissolved in a mixture of methanol and acetone and chromatographed on silica using a mixture of equal volumes of methanol and acetone as eluent. The appropriate eluate was evaporated in vacuo to give 0.37 g of the title compound as an oil.
En del av denna olja kristalliserades i Ä-metylpentan-2-on, var- vid man erhöll kristaller med en smältpunkt av 68-7000. Ingen smältpunktssänkning erhölls när produktkrístallerna blandades med ett prov framställt enligt den metod som beskrives i exempel 15 i den brittiska patentskriften 1 565 966.A portion of this oil was crystallized from Ä-methylpentan-2-one to give crystals, m.p. 68-7000. No melting point drop was obtained when the product crystals were mixed with a sample prepared according to the method described in Example 15 of British Patent Specification 1,565,966.
Claims (4)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8000580 | 1980-01-08 | ||
| GB8000581 | 1980-01-08 | ||
| GB8039336 | 1980-12-08 |
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| SE8100074L SE8100074L (en) | 1981-07-09 |
| SE449747B true SE449747B (en) | 1987-05-18 |
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| SE8502780A SE460604B (en) | 1980-01-08 | 1985-06-05 | AZIRIDE DERIVATIVES AND PROCEDURES FOR ITS PREPARATION |
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| JP (1) | JPH02167259A (en) |
| AR (1) | AR225940A1 (en) |
| AT (1) | AT376966B (en) |
| CH (1) | CH650257A5 (en) |
| DE (1) | DE3100364A1 (en) |
| DK (1) | DK157865C (en) |
| ES (1) | ES498389A0 (en) |
| FI (1) | FI80450C (en) |
| FR (1) | FR2473044A1 (en) |
| HU (1) | HU182272B (en) |
| NL (1) | NL8100068A (en) |
| PT (1) | PT72320B (en) |
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| DE3213509A1 (en) * | 1982-04-10 | 1983-10-20 | Basf Ag, 6700 Ludwigshafen | N-SUBSTITUTED IMIDAZOLE DERIVATIVES, THEIR PRODUCTION, THE MEDICINES CONTAINING THEM AND THEIR USE |
| YU42819B (en) * | 1982-11-22 | 1988-12-31 | Lek Tovarna Farmacevtskih | Process for preparing n-/2-///5-(dimethyl-amino)-methyl-2-furanyl/methyl/thio/ethyl-n'-methyl-2-nitro-1,1-ethene diamine |
| NL8303965A (en) * | 1982-12-08 | 1984-07-02 | Degussa | NEW FOOD DIAMINE AND GUANIDINE DERIVATIVES; METHOD FOR PREPARING THEREOF MEDICINES CONTAINING THEM; METHOD FOR PREPARING SUCH MEDICINES; APPLICATION OF THE COMPOUNDS FOR THE PREPARATION OF MEDICINAL PRODUCTS AND IN MEDICINE. |
| DE3343884A1 (en) * | 1982-12-08 | 1984-06-14 | Degussa Ag, 6000 Frankfurt | Novel ethenediamine and guanidine derivatives |
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| GB1565966A (en) * | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
| IL56265A (en) | 1977-12-28 | 1982-08-31 | Om Lab Sa | Process for preparing imidazolyl methylthio guanidine derivatives and a novel intermediate therefor |
| NO784350L (en) * | 1977-12-30 | 1979-07-03 | Crc Ricerca Chim | PROCEDURE FOR ALKYLATION OF 4 (5) -MERCAPTOMETHYL-IMIDAZOLES WITH AZIRIDINE DERIVATIVES |
| ZA792608B (en) * | 1978-05-30 | 1980-06-25 | Smith Kline French Lab | Nitro compounds |
| NO811501L (en) * | 1980-05-13 | 1981-11-16 | Crc Ricerca Chim | PROCEDURE FOR THE PREPARATION OF ETHENDIAMINE DERIVATIVES, AND INTERMEDIATES FOR THESE |
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1981
- 1981-01-07 PT PT7232081A patent/PT72320B/en unknown
- 1981-01-08 DE DE19813100364 patent/DE3100364A1/en active Granted
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Also Published As
| Publication number | Publication date |
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| DK157865C (en) | 1990-07-30 |
| JPH0346465B2 (en) | 1991-07-16 |
| AR225940A1 (en) | 1982-05-14 |
| DE3100364C2 (en) | 1989-12-28 |
| DE3100364A1 (en) | 1981-11-19 |
| ES8200673A1 (en) | 1981-11-16 |
| AT376966B (en) | 1985-01-25 |
| FI80450B (en) | 1990-02-28 |
| YU2781A (en) | 1983-06-30 |
| FR2473044B1 (en) | 1984-04-13 |
| SE8502780L (en) | 1985-06-05 |
| FI810039L (en) | 1981-07-09 |
| PT72320A (en) | 1981-02-01 |
| YU42372B (en) | 1988-08-31 |
| ATA3781A (en) | 1984-06-15 |
| DK7181A (en) | 1981-07-09 |
| SE8100074L (en) | 1981-07-09 |
| FI80450C (en) | 1990-06-11 |
| FR2473044A1 (en) | 1981-07-10 |
| SE460604B (en) | 1989-10-30 |
| JPH02167259A (en) | 1990-06-27 |
| PT72320B (en) | 1982-07-23 |
| DK157865B (en) | 1990-02-26 |
| HU182272B (en) | 1983-12-28 |
| CH650257A5 (en) | 1985-07-15 |
| ES498389A0 (en) | 1981-11-16 |
| NL8100068A (en) | 1981-08-03 |
| SE8502780D0 (en) | 1985-06-05 |
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