DK157865B - PROCEDURE FOR THE PREPARATION OF RANITIDINE AND ETHYLENIMINO DERIVATIVES FOR USE AS THE PRESENT MATERIAL OF THE PROCEDURE - Google Patents
PROCEDURE FOR THE PREPARATION OF RANITIDINE AND ETHYLENIMINO DERIVATIVES FOR USE AS THE PRESENT MATERIAL OF THE PROCEDURE Download PDFInfo
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- 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
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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
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Description
iin
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Den foreliggende opfindelse a„g4r en særllg fremgangsmåde til frem-stilling af furanderivatet med formlen IThe present invention provides a particular process for preparing the furan derivative of formula I
/F\ CHN02/ F \ CHN02
(CH ) NCH ---"Nv II(CH) NCH --- "Nv II
2 ^^ch2sch2ch2nhcnhch3 I2 ^^ ch2sch2ch2nhcnhch3 I
der er kendt som ranitidin, og som er bestemt i britisk patentskrift nr. 1.565.966 som en kraftig og selektiv H2-antagonist.known as ranitidine, and which is disclosed in British Patent No. 1,565,966 as a potent and selective H2 antagonist.
5 I ovennævnte britiske patentskrift nr. 1.565.966 beskrives der forskellige metoder til fremstilling af ranitidin. Således beskrives der på side 6 en reaktion mellem på den ene side furfurylthiol og på den anden side ω-bromalkylphthalimid. I fransk patentskrift nr. 2.413.373 beskrives en proces til fremstilling af cimetidin og en analog deraf, 10 ved hvilken proces en tilsvarende imidazolylmethylthiol omsættes med en passende substitueret aziridin.5 British Patent Specification No. 1,565,966 discloses various methods for the preparation of ranitidine. Thus, a reaction between furfurylthiol on the one hand and ω-bromoalkylphthalimide on the other is described on page 6. French Patent No. 2,413,373 discloses a process for the preparation of cimetidine and an analog thereof, wherein the process of a corresponding imidazolylmethylthiol is reacted with a suitably substituted aziridine.
I modsætning til cimetidin har ranitidin derimod en stærkt reaktiv ethendiaminfunktion, og det ville derfor forventes, at en til fremstilling af ranitidin på passende måde substitueret aziridin ville 15 være meget ustabil og ville gennemgå omlejringsreaktioner, der ville gøre en sådan reaktion vanskelig eller umulig.In contrast to cimetidine, ranitidine, on the other hand, has a highly reactive ethylene diamine function, and it would therefore be expected that an aziridine substitutably substituted for ranitidine would be highly unstable and undergo rearrangement reactions that would render such a reaction difficult or impossible.
Eftersom en til fremstilling af ranitidin passende substitueret thiol, i kraft af sin dimethylaminomethylfunktion, er væsentlig mere basisk end den i det franske patentskrift beskrevne imidazolylmethyl-20 thiol og endnu mere basisk end den i det britiske patentskrift beskrevne usubstituerede furanmethylthiol, ville det, eftersom det er kendt, at thioler under basiske betingelser autooxiderer til dannelse af disulfider, forventes, at den dimethylaminomethylsubstituerede furanmethylthiol ville have meget dårlig stabilitet og at dens ten-Since a substituted thiol suitable for the preparation of ranitidine, by virtue of its dimethylaminomethyl function, is substantially more basic than the imidazolylmethylthiol described in the French patent and even more basic than the unsubstituted furan methylthiol described in the British patent, it would It is known that, under basic conditions, thiols auto-oxidize to form disulfides, it is expected that the dimethylaminomethyl-substituted furan methylthiol would have very poor stability and that its
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2 dens til autooxidation ville gøre det umuligt at anvende den til fremstilling af ranitidin i rimeligt udbytte.2 for auto-oxidation would make it impossible to use it to produce ranitidine in reasonable yield.
Det har nu overraskende vist sig, at 5-[(dimethylamino)methyl]-2-fu-ranmethanthiol er i stand til at reagere med et alkyleringsmiddel med 5 den almene formel III nedenfor under dannelse af ranitidin i godt udbytte.It has now surprisingly been found that 5 - [(dimethylamino) methyl] -2-furran methanethiol is capable of reacting with an alkylating agent of general formula III below to give ranitidine in good yield.
Den foreliggende opfindelse angår således en fremgangsmåde til fremstilling af furanderivatet med formlen I, hvilken fremgangsmåde er ejendommelig ved, at en thiol med formlen IIThe present invention thus relates to a process for preparing the furan derivative of formula I, which is characterized in that a thiol of formula II
(ch3)2nch2(CH3) 2nch2
CHjSH IICH 2 SH II
10 omsættes med et alkyleringsmiddel med den almene formel III10 is reacted with an alkylating agent of the general formula III
|HN02| HN02
RjRjNCNHCI^RjRjNCNHCI ^
IIIIII
hvor betegner gruppen -CH2CH2L, hvor L er en fraspaltelig enhed, og R2 betegner hydrogen, eller R^ og R2 sammen med det nitrogenatom, til hvilket de er bundet, danner en ethyleniminogruppe.where the group represents -CH 2 CH 2 L, where L is a leaving group and R 2 represents hydrogen, or R 2 and R 2 together with the nitrogen atom to which they are attached form an ethyleneimino group.
Et eksempel på en egnet fraspaltelig enhed L er et halogenatom, idet 15 chlor foretrækkes.An example of a suitable leaving group L is a halogen atom, with chlorine being preferred.
Med fremgangsmåden ifølge opfindelsen tilvejebringes en særlig og nyttig fremgangsmåde til fremstilling af forbindelsen ranitidin.The process of the invention provides a special and useful process for the preparation of the compound ranitidine.
Når R^ betegner gruppen -CH2CH2L, og R2 betegner hydrogen, kan fremgangsmåden ifølge opfindelsen udføres i et egnet opløsningsmiddel 20 såsom vand, vandig tetrahydrofuran, dimethylf ormamid, en alkanol, f.eks. methanol, eller et ketonisk opløsningsmiddel såsom acetone, eventuelt med tilsætning af vand. Omsætningen udføres fortrinsvis iWhere R 1 represents the group -CH 2 CH 2 L and R 2 represents hydrogen, the process of the invention may be carried out in a suitable solvent such as water, aqueous tetrahydrofuran, dimethylformamide, an alkanol, e.g. methanol, or a ketonic solvent such as acetone, optionally with the addition of water. The reaction is preferably carried out in
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3 nærværelse af en base såsom en uorganisk base, f.eks. et alkalime-talcarbonat eller -hydroxid såsom kaliumcarbonat eller kalium- eller natriumhydroxid, et alkoxid, f.eks. natriummethoxid, eller en tertiær amin, f.eks. triethylamin, ved en passende temperatur, f.eks. inden 5 for området fra 10 til 80°C. Omsætningen udføres fortrinsvis i en inert atmosfære, f.eks. under nitrogen. Ved en modifikation af fremgangsmåden kan thiolen med formlen II omsættes med et alkylerings-middel III i et tofasesystem under anvendelse af f.eks. chloroform og vand i nærværelse af en faseovergangskatalysator, f.eks. et kvater-10 nært ammoniumsalt såsom benzyltriethylammoniumchlorid, og en base, f.eks. natriumhydroxid.3 the presence of a base such as an inorganic base, e.g. an alkali metal carbonate or hydroxide such as potassium carbonate or potassium or sodium hydroxide, an alkoxide, e.g. sodium methoxide, or a tertiary amine, e.g. triethylamine, at an appropriate temperature, e.g. within 5 for the range of 10 to 80 ° C. The reaction is preferably carried out in an inert atmosphere, e.g. under nitrogen. In a modification of the process, the thiol of formula II can be reacted with an alkylating agent III in a two-phase system using e.g. chloroform and water in the presence of a phase transition catalyst, e.g. a quaternary ammonium salt such as benzyl triethyl ammonium chloride; and a base, e.g. sodium hydroxide.
Særlig fordelagtige betingelser for udførelse af alkyleringsomsætningen omfatter behandling af thiolen med formlen II med alkylerings-midlet III, hvor betegner gruppen -CI^C^Cl, og R£ betegner hydro-15 gen, enten i nærværelse af et alkalimetalhydroxid, f.eks. kaliumhydroxid, i vand eller i nærværelse af kaliumcarbonat under anvendelse af vandig tetrahydrofuran som opløsningsmiddel. Omsætningen udføres med fordel ved stuetemperatur og under en nitrogenatmosfære.Particularly advantageous conditions for carrying out the alkylation reaction include treating the thiol of formula II with the alkylating agent III, wherein the group represents -Cl 2 C 2 Cl and R 5 represents hydrogen, either in the presence of an alkali metal hydroxide, e.g. potassium hydroxide, in water or in the presence of potassium carbonate using aqueous tetrahydrofuran as solvent. The reaction is advantageously carried out at room temperature and under a nitrogen atmosphere.
Når og R^ sammen med det nitrogenatom, til hvilket de er knyttet, 20 danner en ethyleniminogruppe, kan omsætningen udføres i nærværelse eller fraværelse af et opløsningsmiddel. Egnede opløsningsmidler omfatter vand, en alkanol, f.eks. methanol, og dimethylformamid.When and R 2 together with the nitrogen atom to which they are attached form an ethyleneimino group, the reaction may be carried out in the presence or absence of a solvent. Suitable solvents include water, an alkanol, e.g. methanol, and dimethylformamide.
Omsætningen udføres fortrinsvis under opvarmning, f.eks. ved 100°C, og i en inert atmosfære, f.eks. under nitrogen.The reaction is preferably carried out under heating, e.g. at 100 ° C, and in an inert atmosphere, e.g. under nitrogen.
25 Thiolen II kan dannes in situ ud fra et syreadditionssalt såsom et oxalatsalt ved behandling med base. Thiolen II kan alternativt, når omsætningen udføres i nærværelse af en base, dannes in situ ud fra isothiourinstoffet IVThe thiol II can be formed in situ from an acid addition salt such as an oxalate salt by treatment with base. Alternatively, when the reaction is carried out in the presence of a base, the thiol II can be formed in situ from the isothiourea IV
FF
(CH3) 2nch2 CH2SCNHj IV(CH3) 2nch2 CH2SCNHj IV
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4 eller et salt deraf, f.eks. bismaleatsaltet, ved hydrolyse under omsætningens basiske betingelser.4 or a salt thereof, e.g. the bismaleate salt, by hydrolysis under the basic conditions of the reaction.
Thiolen med formlen II kan fremstilles ved at omsætte den tilsvarende alkohol med formlen VThe thiol of formula II can be prepared by reacting the corresponding alcohol of formula V
(CH3) 2nch2 Q “^ch2oh v 5 med thiourinstof i nærværelse af en koncentreret syre såsom koncentreret saltsyre til dannelse af isothiourinstoffet IV, som derefter omdannes til thiolen med formlen II ved behandling med en base såsom natriumcarbonat eller 5N natriumhydroxid, fortrinsvis i nærværelse af en antioxidant såsom natriumdithionit eller natriumetabisulfit. Når 10 den først er isoleret, kan den således dannede fri base omdannes til et stabilt syreadditionssalt ved behandling med en hensigtsmæssig syre, især oxalsyre, fortrinsvis i et opløsningsmiddel såsom tetrahy-drofuran.(CH 3) 2 nch 2 Q 2 CH 2 OH v 5 with thiourea in the presence of a concentrated acid such as concentrated hydrochloric acid to form the isothiourea 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 etabisulfite. Once isolated, the free base thus formed can be converted to a stable acid addition salt by treatment with a suitable acid, especially oxalic acid, preferably in a solvent such as tetrahydrofuran.
Hvis det ønskes at isolere isothiourinstoffet IV, isoleres dette også 15 fortrinsvis i form af et stabilt salt, f.eks. bismaleatet, ved behandling med en hensigtsmæssig syre, fortrinsvis i et opløsningsmiddel såsom tetrahydrofuran.If it is desired to isolate the isothiourea IV, this is also preferably isolated in the form of a stable salt, e.g. bismaleate, by treatment with a suitable acid, preferably in a solvent such as tetrahydrofuran.
Forbindelsen med formlen III, hvor betegner hvor L betegThe compound of formula III, where denotes where L denotes
ner halogen, f.eks. chlor, og R£ betegner hydrogen, kan fremstilles 20 ved at omsætte en forbindelse med den almene formel VIhalogen, e.g. chlorine, and R R represents hydrogen, can be prepared by reacting a compound of general formula VI
chno2 II vi L’CNHCHjchno2 II vi L'CNHCHj
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5 hvor L' betegner en fraspaltelig enhed, f.eks. methylthio, med en halogenalkylamin såsom chlorethylamin, fortrinsvis i form af et salt, f.eks. et hydrochlorid. Omsætningen udføres i et egnet opløsningsmiddel såsom vand i nærværelse af en base, f.eks. triethylamin, og 5 fortrinsvis ved forhøjet temperatur, f.eks. ved ca. 100°C.5 wherein L 'represents a leaving group, e.g. methylthio, with a haloalkylamine such as chloroethylamine, preferably in the form of a salt, e.g. a hydrochloride. The reaction is carried out in a suitable solvent such as water in the presence of a base, e.g. triethylamine, and preferably at elevated temperature, e.g. at about. 100 ° C.
Forbindelsen med formlen III, hvor R^R^N betegner en ethylenimino-gruppe, kan fremstilles ved at omsætte ethylenimin med en nitro-ethylenamin med den almene formel VIIThe compound of formula III wherein R 1 R 2 N represents an ethyleneimino group can be prepared by reacting ethyleneimine with a nitroethylenamine of general formula VII
CHN02CHN02
L"-CNHCH3 VIIL "-CNHCH3 VII
hvor L" betegner en fraspaltelig enhed, f.eks. en ^-alkoxygruppe 10 eller en ^-alkylthiogruppe, fortrinsvis methylthio. Omsætningen kan udføres i et egnet aprot opløsningsmiddel såsom acetonitril.wherein L "represents a leaving group, for example, a ^ -alkoxy group 10 or a ^ -alkylthio group, preferably methylthio. The reaction may be carried out in a suitable aprotic solvent such as acetonitrile.
Forbindelsen med formlen III, hvor R^R^N betegner en ethylenimino-gruppe, dvs. forbindelsen med formlen VIIIThe compound of formula III wherein R 1 R 2 N represents an ethyleneimino group, i. compound of formula VIII
CH, CHNO- II 2CH, CHNO-II 2
J>N-CNHCH3 VIIIJ> N-CNHCH3 VIII
ch2 er hidtil ukendt, og opfindelsen angår også forbindelsen med formlen 15 VIII til anvendelse ved fremgangsmåden ifølge opfindelsen.ch2 is novel and the invention also relates to the compound of formula VIII for use in the process of the invention.
Thiolen med formlen II og isothiourinstoffet med formlen IV er ikke særlig stabile, men det har vist sig, at de kan stabiliseres ved at omdanne dem til en syreadditionssaltform. Eksempler på sådanne stabile syreadditionssalte omfatter hydrochlorider, sulfater, alkyl- og 20 arylsulfonater, acetater, fumarater, maleater og benzoater. Et foretrukket syreadditionssalt af thiolen med formlen II er oxalatet, ogThe 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 into an acid addition salt form. Examples of such stable acid addition salts include 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
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6 et foretrukket syreadditionssalt af isothiourinstoffet IV er bismale-atet.6 a preferred acid addition salt of the isothiourea IV is bismale.
Fremgangsmåden ifølge den foreliggende opfindelse belyses nærmere ved følgende eksempler, medens fremstilling 1-5 illustrerer fremstilling 5 af mellemprodukter:The process of the present invention is further illustrated by the following examples, while Preparation 1-5 illustrates preparation 5 of intermediates:
Fremstilling 1.Preparation 1.
1- (((5- ( (Dime thylamino)me thyl) -2-furanyl)methyl) thio)methanimidamid, maleat (1:2).1- (((5- ((Dime thylamino) methyl) -2-furanyl) methyl) thio) methanimidamide, maleate (1: 2).
3,1 g 5-((dimethylamino)methyl)-2-furanmethanol sættes gradvis til en 10 opløsning af 1,53 g thiourinstof i 5 ml koncentreret saltsyre. Efter henstand ved stuetemperatur i 18 timer opvarmes opløsningen ved 98 -100°C i 30 minutter. Opløsningen afkøles, der tilsættes 100 ml tetra-hydrofuran og overskud af vandfrit natriumcarbonat, og efter 30 minutter filtreres blandingen. Til filtratet sættes en opløsning af 15 4,65 g maleinsyre i 40 ml tørt tetrahydrofuran, og det faste stof, der udskilles, filtreres, vaskes med tetrahydrofuran og ether, hvorved fås 8,1 g af den i overskriften nævnte forbindelse, smeltepunkt 144 - 145°G.3.1 g of 5 - ((dimethylamino) methyl) -2-furan methanol is gradually added to a solution of 1.53 g of thiourea in 5 ml of concentrated hydrochloric acid. After standing at room temperature for 18 hours, the solution is heated at 98-100 ° C for 30 minutes. The solution is cooled, 100 ml of tetrahydrofuran and excess anhydrous sodium carbonate are added and the mixture is filtered after 30 minutes. To the filtrate is added a solution of 4.65 g of maleic acid in 40 ml of dry tetrahydrofuran, and the solid which is separated is filtered, washed with tetrahydrofuran and ether to give 8.1 g of the title compound, mp 144 - 145 ° G.
Fremstilling 2.Preparation 2.
20 5-((Dimethylamino)methyl)-2-furanmethanthiol, oxalat (1:1).5 - ((Dimethylamino) methyl) -2-furan methanethiol, oxalate (1: 1).
7,76 g 5-((dimethylamino)methyl)-2-furanmethanol sættes gradvis til en opløsning af 3,81 g thiourinstof i 12,5 ml koncentreret saltsyre.5.76 g of 5 - ((dimethylamino) methyl) -2-furan methanol is gradually added to a solution of 3.81 g of thiourea in 12.5 ml of concentrated hydrochloric acid.
Efter 18 timer opvarmes opløsningen i 30 minutter ved 98 - 100°C og inddampes til en lille mængde. En opløsning af 10 g natriumhydroxid i 25 50 ml vand og 10 g natriumdithionit tilsættes, og efter 1 time ek- straheres opløsningen seks gange med hver gang 50 ml ether. Til den vandige fraktion sættes 35 g borsyre, og suspensionen ekstraheres fire gange med hver gang 50 ml ether. Til de forenede etheriske ekstrakter sættes 2 g natriumdithionit og overskud af vandfrit na-After 18 hours, the solution is heated for 30 minutes at 98-100 ° C and evaporated to a small amount. A solution of 10 g of sodium hydroxide in 50 ml of water and 10 g of sodium dithionite is added, and after 1 hour the solution is extracted six times with 50 ml of ether each time. To the aqueous fraction is added 35 g of boric acid and the suspension is extracted four times with 50 ml of ether each time. To the combined ethereal extracts are added 2 g of sodium dithionite and anhydrous anhydrous excess.
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7 triumcarbonat. Efter 3 timer filtreres blandingen ned i en opløsning af 6,3 g oxalsyre i 60 ml tørt tetrahydrofuran.7 triacarbonate. After 3 hours, the mixture is filtered into a solution of 6.3 g of oxalic acid in 60 ml of dry tetrahydrofuran.
Det faste stof, der udskilles, frafiltreres, vaskes med tetrahydrofu-ran og tørres, hvorved fås 5,84 g af den i overskriften nævnte for-5 bindelse, smeltepunkt 116,5 - 118°C.The solid which is separated is filtered off, washed with tetrahydrofuran and dried to give 5.84 g of the title compound, mp 116.5 - 118 ° C.
Fremstilling 3.Preparation 3.
N-(2-Chlorethyl)-N'-methyl-2-nitro-l,1-ethylendiamin.N- (2-Chloroethyl) -N'-methyl-2-nitro-l, 1-ethylenediamine.
Til en opløsning af 5,93 g N-methyl-(l-mettiylthio)-2-nitroethylenamin og 18,56 g 2-chlorethanamirihydrochlorid i 4 ml vand ved 98 -100°C 10 sættes 24 ml triethylamin. Blandingen omrøres ved 98 - 100°C i 10 minutter, og et vakuum (12 - 20 mm) tilsluttes i 50 minutter. Der tilsættes 8 ml vand, og blandingen opvarmes i vakuum ved 98 - 100°C i 20 minutter. 200 ml acetone og overskud af vandfrit magnesiumsulfat sættes til remanensen, og suspensionen opvarmes under tilbagesvaling 15 i 45 minutter. Det faste stof frafiltreres og vaskes tre gange med hver gang 50 ml varm acetone. De forenede filtrat- og vaskevæsker afkøles, og det resulterende krystallinske bundfald isoleres ved filtrering. Filtratet inddampes til 100 ml, det faste stof, der udskilles, frafiltreres, og filtratet inddampes til en lille mængde 20 og chromatograferes (siliciumdioxid/acetone). Det relevante eluat inddampes i vakuum, remanensen suspenderes i ethylacetat:ether (1:4) og filtreres, hvorved fås 2,8 g af den i overskriften nævnte forbindelse, smeltepunkt 113 - 115°C.To a solution of 5.93 g of N-methyl- (1-methylthio) -2-nitroethylenamine and 18.56 g of 2-chloroethanami hydrochloride in 4 ml of water at 98-100 ° C is added 24 ml of triethylamine. The mixture is stirred at 98-100 ° C for 10 minutes and a vacuum (12-20 mm) is sealed for 50 minutes. 8 ml of water are added and the mixture is heated in vacuo at 98-100 ° C for 20 minutes. 200 ml of acetone and excess anhydrous magnesium sulfate are added to the residue and the suspension is heated under reflux for 45 minutes. The solid is filtered off and washed three times with 50 ml of hot acetone each time. The combined filtrate and washings are cooled and the resulting crystalline precipitate is isolated by filtration. The filtrate is evaporated to 100 ml, the solid that is separated is filtered off and the filtrate is evaporated to a small amount and chromatographed (silica / acetone). The relevant eluate is evaporated in vacuo, the residue is suspended in ethyl acetate: ether (1: 4) and filtered to give 2.8 g of the title compound, mp 113 - 115 ° C.
Tyndtlagschromatografi (siliciumdioxid;2-butanon): R^.-værdi 0,4.Thin layer chromatography (silica; 2-butanone): R f value 0.4.
25 Fremstilling 4.Preparation 4.
N-Methyl-a-(nitromethylen)-1-aziridin-methanamin.N-methyl-a- (nitromethylene) -1-aziridine-methanamine.
En opløsning af 0,47 g ethylenimin og 1,48 g N-methyl-(l-methylthio)- 2-nitroethylenamin i 5 ml acetonitril omrøres ved stuetemperatur i 2A solution of 0.47 g of ethyleneimine and 1.48 g of N-methyl- (1-methylthio) -2-nitroethylenamine in 5 ml of acetonitrile is stirred at room temperature for 2 hours.
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8 dage. Suspensionen inddampes i vakuum ved stuetemperatur, og remanensen ekstraheres med 100 ml varmt ethylacetat. Ved inddampning af ekstrakten i vakuum fås en remanens, der suspenderes i 50 ml ethylacetat og filtreres. Filtratet inddampes til ca. 5 ml og chromatogra-5 feres (siliciumdioxid/ethylacetat). Det relevante eluat (tyndtlags-chromatografi (siliciumdioxid/ethylacetat): R^-værdi 0,28) inddampes i vakuum, hvorved fås 0,33 g af den i overskriften nævnte forbindelse, smeltepunkt 118 - 119°C.8 days. The suspension is evaporated in vacuo at room temperature and the residue is extracted with 100 ml of hot ethyl acetate. Evaporation of the extract in vacuo gives a residue which is suspended in 50 ml of ethyl acetate and filtered. The filtrate is evaporated to ca. 5 ml and chromatographed (silica / ethyl acetate). The relevant eluate (thin layer chromatography (silica / ethyl acetate): R 2 value 0.28) is evaporated in vacuo to give 0.33 g of the title compound, mp 118 - 119 ° C.
Fremstilling 5.Preparation 5.
10 5-((Dimethylamino)methyl)-2-furanmethanthiol, oxalat (1:1).5 - ((Dimethylamino) methyl) -2-furan methanethiol, oxalate (1: 1).
En blanding af 83,5 g kaliumcarbonat, 22,9 g natriummetabisulfit og 26,73 g 1-(((5-((dimethylamino)methyl)-2-furanyl)methyl)thio)methan-imidamid, maleat (1:2) i 140 ml vand og 160 ml ether omrøres vinder en nitrogenatmosfære ved stuetemperatur i 24 timer. 10 g vandfrit natri-15 umcarbonat tilsættes, og efter omrøring i yderligere 2 timer fraskilles etherfraktionen og vaskes med en opløsning af 5 g natriummetabisulfit og 8 g kaliumcarbonat i 60 ml vand. Etherekstrakten tørres over natriumsulfat i 1 time og filtreres ned i en opløsning af 7,6 g oxalsyre i 100 ml tetrahydrofuran. Det faste stof, der udskil-20 les (13,33 g), krystalliseres af tetrahydrofuran, hvorved fås 12,20 g af den i overskriften nævnte forbindelse, smeltepunkt 116,5 -119°C.A mixture of 83.5 g of potassium carbonate, 22.9 g of sodium metabisulfite and 26.73 g of 1 - (((5 - ((dimethylamino) methyl) -2-furanyl) methyl) thio) methane imidamide maleate (1: 2 ) in 140 ml of water and 160 ml of ether, a nitrogen atmosphere is stirred at room temperature for 24 hours. 10 g of anhydrous sodium carbonate are added and after stirring for an additional 2 hours the ether fraction is separated and washed with a solution of 5 g of sodium metabisulphite and 8 g of potassium carbonate in 60 ml of water. The ether extract is dried over sodium sulfate for 1 hour and filtered into a solution of 7.6 g of oxalic acid in 100 ml of tetrahydrofuran. The solid, which is separated (13.33 g), is crystallized by tetrahydrofuran to give 12.20 g of the title compound, mp 116.5-111 ° C.
Eksempel 1.Example 1.
N-(2-((5-((Dimethylamino)methyl)-2-furanylmethyl) thio)ethyl)-Ν' -methyl-2-nitro-1,1-ethylendiamin.N- (2 - ((5 - ((Dimethylamino) methyl) -2-furanylmethyl) thio) ethyl) -Ν'-methyl-2-nitro-1,1-ethylenediamine.
25 En blanding af 0,9 g N-(2-chlorethyl)-N'-methyl-2-nitro-l,l-ethylen-diamin, 1,3 g 5-((dimethylamino)methyl)-2-furanmethanthiol, oxalat (1:1) og 2,7 g kaliumcarbonat i 10 ml vand og 10 ml tetrahydrofuran omrøres vinder nitrogen ved stuetemperatur i 5 dage. Suspensionen inddampes i vakuum, remanensen blandes med 40 ml vand, og suspen-30 sionen ekstraheres to gange med hver gang 30 ml ether. Den vandigeA mixture of 0.9 g of N- (2-chloroethyl) -N'-methyl-2-nitro-1,1-ethylene diamine, 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 are stirred to obtain nitrogen at room temperature for 5 days. The suspension is evaporated in vacuo, the residue is mixed with 40 ml of water and the suspension is extracted twice with 30 ml of ether each time. The watery
DK 157865 BDK 157865 B
9 fraktion inddampes i vakuum, og remanensen inddampes to gange med hver gang 10 ml ethanol. 20 ml tetrahydrofuran, magnesiumsulfat og affarvende aktivkul tilsættes, og efter 1 time filtreres blandingen.9 fraction is evaporated in vacuo and the residue is evaporated twice with 10 ml of ethanol each time. 20 ml of tetrahydrofuran, magnesium sulfate and decolorizing activated charcoal are added and after 1 hour the mixture is filtered.
Ved inddampning af filtratet fås 1 g af en olie, der chromatograferes 5 (siliciumdioxid/methanol:0,88 ammoniak (79:1)). Det relevante eluat inddampes, og den olieagtige remanens (0,66 g) ekstraheres med varmt isopropylacetat. Det faste stof, der udskilles, frafiltreres, hvorved fås 0,4 g af den i overskriften nævnte forbindelse, smeltepunkt 65 -68°C der ikke sænkes ved tilblanding af en prøve fremstillet ifølge 10 den i eksempel 15 i britisk patentskrift nr. 1.565.966 beskrevne fremgangsmåde.Evaporation of the filtrate gives 1 g of an oil which is chromatographed 5 (silica / methanol: 0.88 ammonia (79: 1)). The relevant eluate is evaporated and the oily residue (0.66 g) is extracted with hot isopropyl acetate. The solid which is separated is filtered off to give 0.4 g of the title compound, mp 65-68 ° C which is not lowered by admixture of a sample prepared according to Example 15 of British Patent Specification No. 1,565. 966.
Eksempel 2.Example 2.
N-(2-((5-((Dimethylamino)methyl)-2-furanylmethyl)thio)ethyl)-N'-methyl -2-nitro-1,1-ethylendiamin.N- (2 - ((5 - ((Dimethylamino) methyl) -2-furanylmethyl) thio) ethyl) -N'-methyl -2-nitro-1,1-ethylenediamine.
15 En blanding af 2,23 g l-(((5-((dimethylamino)methyl)-2-furanyl)- methyl)thio)methanimidamid, maleat (1:2), 0,9 g N-(2-chlorethyl)- N'-methyl-2-nitro-1,1-ethylendiamin og 3,46 g kaliumcarbonat i 10 ml vand og 10 ml tetrahydrofuran omrøres under nitrogen ved stuetemperatur i 5 dage. Suspensionen inddampes i vakuum; remanensen suspen-20 deres i 50 ml vand og ekstraheres to gange med hver gang 40 ml ether.A mixture of 2.23 g of 1 - (((5 - ((dimethylamino) methyl) -2-furanyl) -methyl) thio) methanimidamide, maleate (1: 2), 0.9 g of N- (2-chloroethyl) ) - N'-methyl-2-nitro-1,1-ethylenediamine and 3.46 g of potassium carbonate in 10 ml of water and 10 ml of tetrahydrofuran are stirred under nitrogen at room temperature for 5 days. The suspension is evaporated in vacuo; the residue is suspended in 50 ml of water and extracted twice with 40 ml of ether each time.
Den vandige fraktion inddampes i vakuum, og der tilsættes magnesiumsulfat og 100 ml tetrahydrofuran. Efter 18 timer filtreres blandingen, og filtratet inddampes, hvorved fås et halvfast stof, som chromatograferes (siliciumdioxid/methanol). Det relevante eluat inddampes i 25 vakuum, hvorved fås 0,3 g af den i overskriften nævnte forbindelse, der har et NMR-spektrum, der er identisk med spektret for det i eksempel 1 fremstillede produkt.The aqueous fraction is evaporated in vacuo and magnesium sulfate and 100 ml of tetrahydrofuran are added. After 18 hours, the mixture is filtered and the filtrate is evaporated to give a semi-solid which is chromatographed (silica / methanol). The relevant eluate is evaporated in vacuo to give 0.3 g of the title compound having an NMR spectrum identical to the spectrum of the product prepared in Example 1.
DK 157865BDK 157865B
1010
Eksempel 3.Example 3
N-(2-((5-((Dimethylamino)methyl)-2-furanylmethyl)thio)ethyl)-N'-methyl -2-nitro-1,1-ethylendiamin.N- (2 - ((5 - ((Dimethylamino) methyl) -2-furanylmethyl) thio) ethyl) -N'-methyl -2-nitro-1,1-ethylenediamine.
Til en blanding af 0,156 5-((dimethylamino)methyl)-2-furanmethan-5 thiol, oxalat (1:1), 0,05 g natriumdithionit og 0,15 g vandfrit natriumcarbonat i 0,4 ml vand sættes 15 ml ether og et overskud af vandfrit natriumcarbonat. Blandingen filtreres, og filtratet inddampes i vakuum. Til remanensen sættes 0,072 g N-methyl-a-(nitromethylen)- 1-aziridinmethanamin og 2 ml methanol, og opløs-10 ningen inddampes til tørhed. Remanensen opvarmes ved 98 - 100°C i 1 1/4 time, og produktet chromatograferes (siliciumdioxid/methanol, 0,88 ammoniak, 79:1). Det relevante eluat inddampes i vakuum, hvorved der fås 0,113 g af den i overskriften nævnte forbindelse, der har et NMR-spektrum, der er identisk med spektret for det i ovenstående 15 eksempler fremstillede produkt.To a mixture of 0.156 5 - ((dimethylamino) methyl) -2-furanmethanethiol, oxalate (1: 1), 0.05 g sodium dithionite and 0.15 g anhydrous sodium carbonate in 0.4 ml water is added 15 ml ether and an excess of anhydrous sodium carbonate. The mixture is filtered and the filtrate is evaporated in vacuo. To the residue is added 0.072 g of N-methyl-α- (nitromethylene) -1-aziridine methanamine and 2 ml of methanol and the solution is evaporated to dryness. The residue is heated at 98-100 ° C for 1 1/4 hour and the product is chromatographed (silica / methanol, 0.88 ammonia, 79: 1). The relevant eluate is evaporated in vacuo to give 0.113 g of the title compound having an NMR spectrum identical to the spectrum of the product prepared in the above 15 examples.
Eksempel 4.Example 4
N-(2-((5-((Dimethylamino)methyl)-2-furanylmethyl) thio)ethyl)-N'-methyl-2-nitro-l,l-ethylendiamin.N- (2 - ((5 - ((Dimethylamino) methyl) -2-furanylmethyl) thio) ethyl) -N'-methyl-2-nitro-1,1-ethylenediamine.
Til en omrørt blanding af 1,31 g 5-((dimethylarnino)methyl)-2-furan-20 methanthiol, oxalat (1:1) og 1,08 g N-(2-chlorethyl)-N'-methyl-2-ni-tro-l,l-ethylendiamin i 20 ml vand ved 45°C sættes under en nitrogenatmosfære en opløsning af 1,04 g kaliumhydroxid i 3 ml vand. Opløsningen omrøres ved 45° C i 2 1/2 time og ved stuetemperatur i 15 timer. Opløsningen inddampes derefter i vakuum, remanensen opløses i 25 vand og en luftstrøm ledes ned i blandingen i 15 minutter. Blandingen ekstraheres to gange med hver gang 15 ml ether, og den vandige fraktion inddampes i vakuum. Til remanensen sættes 70 ml tetrahydrofuran, et overskud af vandfrit natriumcarbonat og affarvende aktivkul. Efter 1 time filtreres blandingen, filtratet inddampes i vakuum, og den 30 olieagtige remanens opløses i 8 ml 4-methylpentan- 2-on. Det faste stof, der udskilles, frafiltreres og vaskes med 4-methylpentan-2-on, hvorved fås 0,72 g af den i overskriften nævnte forbindelse, smelte-To a stirred mixture of 1.31 g of 5 - ((dimethylarino) methyl) -2-furan-methanethiol, oxalate (1: 1) and 1.08 g of N- (2-chloroethyl) -N'-methyl-2 -Nitro-1,1-ethylenediamine in 20 ml of water at 45 ° C is added under a nitrogen atmosphere a solution of 1.04 g of potassium hydroxide in 3 ml of water. The solution is stirred at 45 ° C for 2 1/2 hours and at room temperature for 15 hours. The solution is then evaporated in vacuo, the residue is dissolved in 25 water and an air stream is fed into the mixture for 15 minutes. The mixture is extracted twice with 15 ml of ether each time and the aqueous fraction is evaporated in vacuo. To the residue is added 70 ml of tetrahydrofuran, an excess of anhydrous sodium carbonate and decolorizing activated charcoal. After 1 hour, the mixture is filtered, the filtrate is evaporated in vacuo and the oily residue is dissolved in 8 ml of 4-methylpentan-2-one. The solid which is separated is filtered off and washed with 4-methylpentan-2-one to give 0.72 g of the title compound,
Claims (7)
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8000580 | 1980-01-08 | ||
| GB8000581 | 1980-01-08 | ||
| GB8000581 | 1980-01-08 | ||
| GB8000580 | 1980-01-08 | ||
| GB8039336 | 1980-12-08 | ||
| GB8039336 | 1980-12-08 |
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| Publication Number | Publication Date |
|---|---|
| DK7181A DK7181A (en) | 1981-07-09 |
| DK157865B true DK157865B (en) | 1990-02-26 |
| DK157865C DK157865C (en) | 1990-07-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| DK7181A DK157865C (en) | 1980-01-08 | 1981-01-08 | PROCEDURE FOR THE PREPARATION OF RANITIDINE AND ETHYLENIMINO DERIVATIVES FOR USE AS THE PRESENT MATERIAL OF THE PROCEDURE |
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| Country | Link |
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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) | ES8200673A1 (en) |
| FI (1) | FI80450C (en) |
| FR (1) | FR2473044A1 (en) |
| HU (1) | HU182272B (en) |
| NL (1) | NL8100068A (en) |
| PT (1) | PT72320B (en) |
| SE (2) | SE449747B (en) |
| YU (1) | YU42372B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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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 |
| DE3343884A1 (en) * | 1982-12-08 | 1984-06-14 | Degussa Ag, 6000 Frankfurt | Novel ethenediamine and guanidine derivatives |
| 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. |
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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 |
| GR65283B (en) * | 1977-12-30 | 1980-08-01 | Crc Ricerca Chim | Method for the alkyliosis of 4(5)-merka ptomethyl-imidazoles with aziridin derivatives |
| IL57416A (en) * | 1978-05-30 | 1983-03-31 | Smith Kline French Lab | Nitro compounds,processes for preparing them and compositions containing them |
| FI811376L (en) * | 1980-05-13 | 1981-11-14 | Crc Ricerca Chim | PROCEDURE FOR FRAMSTATING AV N- / 2 - /// 5- (DIALKYLAMINO) -METHYL-2-FURANYL / -METHYL / -THIO / EECL / -N'-ALKYL-2-NITRO-1,1-ETENDIAMINER OCH DERAS MELLANPRODUKTER |
-
1981
- 1981-01-07 PT PT7232081A patent/PT72320B/en unknown
- 1981-01-08 ES ES498389A patent/ES8200673A1/en not_active Expired
- 1981-01-08 AT AT3781A patent/AT376966B/en not_active IP Right Cessation
- 1981-01-08 FR FR8100206A patent/FR2473044A1/en active Granted
- 1981-01-08 DK DK7181A patent/DK157865C/en not_active IP Right Cessation
- 1981-01-08 DE DE19813100364 patent/DE3100364A1/en active Granted
- 1981-01-08 CH CH8681A patent/CH650257A5/en not_active IP Right Cessation
- 1981-01-08 SE SE8100074A patent/SE449747B/en not_active IP Right Cessation
- 1981-01-08 YU YU2781A patent/YU42372B/en unknown
- 1981-01-08 HU HU3981A patent/HU182272B/en unknown
- 1981-01-08 NL NL8100068A patent/NL8100068A/en active Search and Examination
- 1981-01-08 FI FI810039A patent/FI80450C/en not_active IP Right Cessation
- 1981-01-08 AR AR28390081A patent/AR225940A1/en active
-
1985
- 1985-06-05 SE SE8502780A patent/SE460604B/en not_active IP Right Cessation
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1989
- 1989-10-25 JP JP27829589A patent/JPH02167259A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ES498389A0 (en) | 1981-11-16 |
| PT72320B (en) | 1982-07-23 |
| DK7181A (en) | 1981-07-09 |
| SE460604B (en) | 1989-10-30 |
| FR2473044A1 (en) | 1981-07-10 |
| DK157865C (en) | 1990-07-30 |
| SE8502780L (en) | 1985-06-05 |
| FR2473044B1 (en) | 1984-04-13 |
| SE8502780D0 (en) | 1985-06-05 |
| PT72320A (en) | 1981-02-01 |
| JPH0346465B2 (en) | 1991-07-16 |
| SE8100074L (en) | 1981-07-09 |
| DE3100364A1 (en) | 1981-11-19 |
| AR225940A1 (en) | 1982-05-14 |
| JPH02167259A (en) | 1990-06-27 |
| FI810039L (en) | 1981-07-09 |
| ES8200673A1 (en) | 1981-11-16 |
| NL8100068A (en) | 1981-08-03 |
| AT376966B (en) | 1985-01-25 |
| HU182272B (en) | 1983-12-28 |
| ATA3781A (en) | 1984-06-15 |
| YU2781A (en) | 1983-06-30 |
| CH650257A5 (en) | 1985-07-15 |
| DE3100364C2 (en) | 1989-12-28 |
| YU42372B (en) | 1988-08-31 |
| FI80450C (en) | 1990-06-11 |
| FI80450B (en) | 1990-02-28 |
| SE449747B (en) | 1987-05-18 |
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