DK170067B1 - Process for the preparation of amine derivatives - Google Patents
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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
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Description
i DK 170067 B1in DK 170067 B1
Den foreliggende opfindelse angår en fremgangsmåde til fremstilling af aminderivater. N-Methyl-l-alkylthio-2-nitroethen-aminderivater er nyttige mellemprodukter til fremstilling af ranitidin og andre histamin-H2-antagonister indeholdende 5 endegruppen -NHC(=CHN02)NHCH3, fx nizatidin.The present invention relates to a process for the preparation of amine derivatives. N-Methyl-1-alkylthio-2-nitroethene amine derivatives are useful intermediates for the preparation of ranitidine and other histamine H2 antagonists containing the end group -NHC (= CHNO2) NHCH3, e.g. nizatidine.
Sådanne mellemprodukter er hidtil blevet fremstillet ved direkte udskiftning af en enkelt alkylthiogruppe i 2,2-bis-alkylthio-l-nitroethenderivater ved omsætning med methylamin. Denne reaktion har imidlertid ikke selektivitet og fører til 10 N-methyl-l-alkylthio-2-nitroethener forurenet med både uomsat udgangsmateriale og det bis-aminerede biprodukt 2,2-bisme-thylamino-1-nitroethen.Such intermediates have heretofore been prepared by direct replacement of a single alkylthio group into 2,2-bis-alkylthio-1-nitroethene derivatives by reaction with methylamine. However, this reaction does not have selectivity and leads to 10 N-methyl-1-alkylthio-2-nitroethenes contaminated with both unreacted starting material and the bis-aminated by-product 2,2-bismethylamino-1-nitroethene.
I britisk patentskrift nr. 1421792 beskrives fremstillingen af forbindelser med den almene formelBritish Patent No. 1421792 describes the preparation of compounds of the general formula
R2S .NHRR2S .NHR
Xc x ff c 15 hvor X og Y, som kan have samme eller forskellig betydning, hver for sig betegner hydrogen, nitro, cyano eller S02Ar (hvor Ar betegner eventuelt substitueret phenyl), bortset fra, at X og Y ikke begge kan betegne hydrogen, R betegner lavere alkyl, og R2 betegner lavere alkyl eller aralkyl, ved 20 nedenstående reaktionssekvens:Xc x ff c 15 where X and Y, which may have the same or different meaning, each represent hydrogen, nitro, cyano or SO 2 Ar (where Ar represents optionally substituted phenyl), except that X and Y cannot both represent hydrogen , R represents lower alkyl, and R 2 represents lower alkyl or aralkyl, at the following reaction sequence:
CH2XY RN = C=S> /NHR R2Hal R2S. ^NHRCH2XY RN = C = S> / NHR R2Hal R2S. ^ NHR
I „I „
CHXY CCHXY C
^y^ y
Den substituerede methan CH2XY siges at blive omsat med isothiocyanatesteren efter behandling med en stærk base såsom natriumhydrid eller natriumhydroxid. I det eneste specifikke eksempel på denne reaktion, der er beskrevet, omsættes me- DK 170067 B1 2 thylisothiocyanat med malononitril i nærværelse af natriumhydrid og dimethylformamid. Det andet trin i reaktionen udføres ved at tilsætte methyliodid i dimethylformamid.The substituted methane CH2XY is said to react with the isothiocyanate ester after treatment with a strong base such as sodium hydride or sodium hydroxide. In the only specific example of this reaction described, thylisothiocyanate is reacted with malononitrile in the presence of sodium hydride and dimethylformamide. The second step of the reaction is carried out by adding methyl iodide in dimethylformamide.
Chem. Ber. 100, 1967, s. 591-604 beskriver omsætningen mellem ? 5 phenylisothiocyanat med nitromethan, og det fremgår også, atChem. Ber. 100, 1967, pp. 591-604 describes the turnover between? 5 phenylisothiocyanate with nitromethane, and it is also apparent that
omsætningen bør udføres i nærværelse af natriumhydrid i Athe reaction should be carried out in the presence of sodium hydride in A
dimethylformamid. Reaktionen efterfølges af methylering med methyliodid til fremstilling af N-phenyl-l-methylthio-2-nitroethenamin.dimethylformamide. The reaction is followed by methylation with methyl iodide to prepare N-phenyl-1-methylthio-2-nitroethenamine.
10 Anvendelsen af natriumhydrid i dimethylformid som angivet i de ovennævnte publikationer, er uegnet til fremstilling i stor skala på grund af de risici, der er forbundet med kombinationen af disse reagenser.The use of sodium hydride in dimethylformide as disclosed in the above publications is unsuitable for large scale preparation due to the risks associated with the combination of these reagents.
Den foreliggende opfindelse angår en fremgangsmåde til frem-15 stilling af N-methyl-l-alkylthio-2-nitroethenaminderivat med den almene formel IIThe present invention relates to a process for the preparation of N-methyl-1-alkylthio-2-nitroethenamine derivative of the general formula II
R.S 1 \R.S 1 \
C=CHN0o IIC = CHNO 2
/ 2/ 2
CH3NHCH3NH
hvor Rx betegner en alkylgruppe med 1-4 carbonatomer, hvilken fremgangsmåde er ejendommelig ved, at en forbindelse 20 med den almene formel Iwherein Rx represents an alkyl group of 1-4 carbon atoms, the process being characterized in that a compound 20 of the general formula I
QSQS
^C=CHN0? I^ C = CHN0? IN
CH-NITNIT-CH
t DK 170067 B1 3 fremstilles ved, at methylisothiocyanat omsættes med carban-ionen af nitromethan i nærværelse af dimethylsulfoxid som opløsningsmiddel, eventuelt i nærværelse af et co-opløsnings-middel, i hvilken formel I Q betegner et hydrogenatom eller 5 en kation, der er afledt af en egnet base, der anvendes til dannelse af carbanionen af nitromethan in situ, hvorefter forbindelsen med formlen I omsættes med et egnet .alkylerings-middel til dannelse af N-methyl-l-alkylthio-2-nitroethenamin-derivatet med formlen II, hvorhos reaktionen med alkylerings-10 midlet eventuelt udføres på den in situ fremstillede forbindelse med formlen I.DK 170067 B1 3 is prepared by reacting methyl isothiocyanate with the carban ion of nitromethane in the presence of dimethyl sulfoxide as solvent, optionally in the presence of a co-solvent in which formula IQ represents a hydrogen atom or a cation derived of a suitable base used to form the carbanion of nitromethane in situ, after which the compound of formula I is reacted with a suitable alkylating agent to form the N-methyl-1-alkylthio-2-nitroethenamine derivative of formula II, wherein optionally, the reaction with the alkylating agent is carried out on the in situ prepared compound of formula I.
Forbindelsen med formlen I, hvor Q betegner et hydrogenatom, kan fremstilles ud fra en forbindelse med formlen I, hvor Q betegner en kation, ved tilsætning af éet ækvivalent af en 15 egnet syre.The compound of formula I, wherein Q represents a hydrogen atom, can be prepared from a compound of formula I wherein Q represents a cation, by adding one equivalent of a suitable acid.
Forbindelsen med formlen I, hvor Q er hydrogen eller en kation, behandles ifølge opfindelsen med et relevant alky-leringsmiddel, fx et alkylhalogenid (fx methylbromid eller methyliodid) eller et dialkylsulfat (fx dimethylsulfat), til 20 fremstilling af et N-methyl-l-alkylthio-2-nitroethenaminderi-vat med den almene formel II.The compound of formula I wherein Q is hydrogen or a cation is treated according to the invention with a relevant alkylating agent, for example an alkyl halide (e.g. methyl bromide or methyl iodide) or a dialkyl sulfate (e.g. dimethyl sulfate), to prepare an N-methyl-1 -alkylthio-2-nitroethenamine derivative of the general formula II.
Det har overraskende vist sig, at dannelsen af forbindelsen med formlen I og således fremstillingen af N-methyl-l-alkyl-thio-2-nitroethenaminderivaterne med den almene formel II 25 forløber med særligt godt udbytte, hvis reaktionen mellem methylisothiocyanat og carbanionen af nitromethan udføres i dimethylsulfoxid som opløsningsmiddel, eventuelt i nærværelse af et co-opløsningsmiddel. Når således reaktionen mellem methylisothiocyanat og nitromethan udføres i nærværelse af 30 natriumhydrid som base, stiger udbyttet fra 22%, når der anvendes dimethylformamid som opløsningsmiddel, til 59%, når der som opløsningsmiddel anvendes dimethylsulfoxid.Surprisingly, it has been found that the formation of the compound of formula I and thus the preparation of the N-methyl-1-alkyl-thio-2-nitroethenamine derivatives of the general formula II 25 proceeds in particularly good yield if the reaction between methyl isothiocyanate and the carbanion of nitromethane is carried out in dimethyl sulfoxide as solvent, optionally in the presence of a co-solvent. Thus, when the reaction between methyl isothiocyanate and nitromethane is carried out in the presence of 30 sodium hydride as a base, the yield increases from 22% when using dimethylformamide as a solvent to 59% when using dimethyl sulfoxide as the solvent.
DK 170067 B1 4DK 170067 B1 4
Forbindelsen med formlen I omsættes fortrinsvis in situ med alkyleringsmidlet, og i dette tilfælde udføres reaktionen generelt også i samme opløsningsmedium.The compound of formula I is preferably reacted in situ with the alkylating agent, and in this case the reaction is generally carried out in the same solvent medium as well.
Egnede co-opløsningsmidler, hvis art afhænger af den anvendte 5 base, omfatter aprote opløsningsmidler (fx dimethylformamid og N-methylpyrrolidinon) og vand.Suitable co-solvents, the nature of which depends on the base used, include aprotic solvents (e.g., dimethylformamide and N-methylpyrrolidinone) and water.
44
Ved en særlig udførelsesform for fremgangsmåden ifølge opfindelsen foretages methylering af forbindelsen med formlen I fremstillet in si tu under anvendelse af et egnet methyl-10 eringsmiddel såsom methyliodid eller dimethylsulfat til dannelse af N-methyl-l-methylthio-2-nitroethenamin, dvs. den forbindelse med formlen II, hvor Rx er methyl.In a particular embodiment of the process according to the invention, methylation of the compound of formula I is prepared in situ using a suitable methylating agent such as methyl iodide or dimethyl sulfate to form N-methyl-1-methylthio-2-nitroethenamine, i.e. the compound of formula II wherein Rx is methyl.
Forbindelserne med formlen I kan forekomme i tautomere former, og formlen I skal forstås således, at den omfatter alle 15 sådanne former.The compounds of formula I may exist in tautomeric forms, and formula I is to be understood to include all 15 such forms.
Fremgangsmåden ifølge den foreliggende opfindelse giver N-methyl-l-alkylthio-2-nitroethenaminer med formlen II i godt udbytte og i en form, der kan anvendes til at fremstille forbindelser såsom ranitidin uden yderligere rensning. Denne 20 fremgangsmåde, ved hvilken der anvendes billige, enkle og kommercielt tilgængelige udgangsmaterialer, kan generelt udføres sikkert i stor skala og under milde betingelser. Fremgangsmåden ifølge opfindelsen er særlig velegnet til fremstilling af N-methyl-l-methylthio-2-nitroethenamin.The process of the present invention provides N-methyl-1-alkylthio-2-nitroethenamines of formula II in good yield and in a form which can be used to prepare compounds such as ranitidine without further purification. This method, using cheap, simple and commercially available starting materials, can generally be safely carried out on a large scale and under mild conditions. The process of the invention is particularly well suited for the preparation of N-methyl-1-methylthio-2-nitroethenamine.
25 Carbanionen af nitromethan fremstilles bekvemt in situ ved at behandle nitromethan med en egnet base. Særlig egnede baser omfatter alkalimetalhydrider, alkalimetalhydroxider og alka-limetalalkoxider, fx natriumhydrid, natriumhydroxid, kaliumhydroxid, natriumethoxid, natriumisopropoxid og kalium-30 tert.butoxid. Der foretrækkes alkalimetalhydroxider, og når basen er et alkalimetalhydroxid, kan den tilsættes i form af en vandig opløsning.The carbanion of nitromethane is conveniently prepared in situ by treating nitromethane with a suitable base. Particularly suitable bases include alkali metal hydrides, alkali metal hydroxides and alkali metal alkoxides, for example sodium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium isopropoxide and potassium tert-butoxide. Alkali metal hydroxides are preferred and when the base is an alkali metal hydroxide it can be added in the form of an aqueous solution.
DK 170067 B1 5DK 170067 B1 5
Hvis der udføres påfølgende reaktion med alkyleringsmidlet på den in situ fremstillede forbindelse med formlen I, anvendes der almindeligvis det samme opløsningsmiddelmedium til alky-leringsreaktionen.If subsequent reaction is carried out with the alkylating agent on the in situ prepared compound of formula I, the same solvent medium is generally used for the alkylation reaction.
5 Reaktionstemperaturen ligger bekvemt i området mellem 0 og 50°C, og reaktionen foretages fortrinsvis ved stuetemperatur.The reaction temperature is conveniently in the range of 0 to 50 ° C, and the reaction is preferably carried out at room temperature.
I et yderligere aspekt angår den foreliggende opfindelse en fremgangsmåde til fremstilling af forbindelser, især histamin -H2- antagonist er, der indeholder en -NHC(=CHN02)NHCH3-10 endegruppe, hvilken fremgangsmåde er ejendommelig ved, at et på den ovenfor beskrevne måde fremstillet N-methyl-1-alkyl-thio-2-nitroethenaminderivat med formlen II omsættes med en egnet amin. I dette aspekt af den foreliggende opfindelse kan ranitidin således fremstilles ud fra 2-[5-(Ν,Ν-dimethylamino-15 methyl)-2-furanmethylthio]ethylamin som aminen, fortrinsvis under anvendelse af N-methyl-l-methylthio-2-nitroethenamin som forbindelsen med forbindelsen med formlen II. Denne reaktion kan udføres i et opløsningsmiddel såsom vand, eventuelt under opvarmning.In a further aspect, the present invention relates to a process for the preparation of compounds, especially histamine -H2- antagonist which contains an -NHC (= CHNO2) NHCH3-10 end group, characterized in that a method as described above prepared N-methyl-1-alkyl-thio-2-nitroethenamine derivative of formula II is reacted with a suitable amine. Thus, in this aspect of the present invention, ranitidine can be prepared from 2- [5- (Ν, Ν-dimethylamino-methyl) -2-furanmethylthio] ethylamine as the amine, preferably using N-methyl-1-methylthio-2 -nitroethenamine as the compound of the compound of formula II. This reaction may be carried out in a solvent such as water, optionally under heating.
20 Opfindelsen belyses nærmere ved nedenstående eksempler: EKSEMPEL 1 N-Methyl-l-methylthio-2-nitroethenamin i) 1,25 g nitromethan blev i løbet af 1 minut sat til en suspension af 1,15 g kaliumhydroxid i flager i 18 ml dime-25 thylsulfoxid (indeholdende 7,5% vand). En opløsning af 1,5 g methylisothiocyanat i 2,5 ml dimethylsulfoxid (indeholdende 7,5% vand) blev tilsat i løbet af 2 minutter, medens temperaturen blev holdt på 20-26°C. Opløsningen blev omrørt i yderligere 1/2 time ved stuetemperatur, og 3,19 g methyliodid 30 blev tilsat dråbevis i løbet af 2 minutter, medens temperaturen blev holdt på 22-24°C. Omrøringen blev fortsat i 1 time ved stuetemperatur, hvorefter opløsningen blev fortyndet med DK 170067 B1 6 200 ml vand og ekstraheret med dichlormethan. De samlede ekstrakter blev vasket med vand og inddampet til tørhed, og remanensen blev krystalliseret af 2-propanol, hvorved man fik 1,5 g af titelforbindelsen (49,4%), smeltepunkt 113-116,5°C.The invention is further illustrated by the following examples: EXAMPLE 1 N-Methyl-1-methylthio-2-nitroethenamine i) 1.25 g of nitromethane was added over 1 minute to a suspension of 1.15 g of potassium hydroxide in flakes in 18 ml of dime. -25 thylsulfoxide (containing 7.5% water). A solution of 1.5 g of methyl isothiocyanate in 2.5 ml of dimethyl sulfoxide (containing 7.5% water) was added over 2 minutes while maintaining the temperature of 20-26 ° C. The solution was stirred for an additional 1/2 hour at room temperature, and 3.19 g of methyl iodide 30 was added dropwise over 2 minutes while maintaining the temperature of 22-24 ° C. Stirring was continued for 1 hour at room temperature, after which the solution was diluted with DK 170067 B1 6 200 ml of water and extracted with dichloromethane. The combined extracts were washed with water and evaporated to dryness, and the residue was crystallized by 2-propanol to give 1.5 g of the title compound (49.4%), mp 113-116.5 ° C.
5 ii) 1,32 g nitromethan i 5 ml dimethylsulfoxid (indeholdende 7,5% vand) blev i løbet af 5 minutter ved 0-5°C sat til 0,52 g natriumhydrid i 20 ml dimethylsulfoxid (indeholdende 7,5% vand). Blandingen fik lov at opvarme til stuetemperatur, og efter yderligere 30 minutters forløb blev 1,58 g methyliso-10 thiocyanat i 5 ml dimethylsulfoxid (indeholdende 7,5% vand) tilsat i løbet af 5 minutter. Blandingen blev behandlet med 3,07 g methyliodid i 5 ml dimethylsulfoxid (indeholdende 7,5% vand), medens temperaturen blev holdt på under 30°C, og den resulterende opløsning blev omrørt natten over. Opløsnings-15 midlet blev fjernet, 50 ml vand blev sat til remanensen, og blandingen blev oparbejdet på den i eksempel 1 i) angivne måde, hvorved man fik 1,88 g af titelforbindelsen (58,7%), smeltepunkt 112-114°C.Ii) 1.32 g of nitromethane in 5 ml of dimethyl sulfoxide (containing 7.5% water) was added to 0.52 g of sodium hydride in 20 ml of dimethyl sulfoxide (containing 7.5% water) over 5 minutes at 0-5 ° C ). The mixture was allowed to warm to room temperature and after a further 30 minutes 1.58 g of methyl isothiocyanate in 5 ml of dimethyl sulfoxide (containing 7.5% water) was added over 5 minutes. The mixture was treated with 3.07 g of methyl iodide in 5 ml of dimethyl sulfoxide (containing 7.5% water) while maintaining the temperature below 30 ° C and the resulting solution stirred overnight. The solvent was removed, 50 ml of water was added to the residue, and the mixture was worked up in the manner indicated in Example 1 i) to give 1.88 g of the title compound (58.7%), mp 112-114 ° C.
iii) 0,62 g nitromethan blev i løbet af 2 minutter dryppet 20 til en suspension af 1,1 g kalium-tert.butoxid i 9 ml tørt dimethylsulfoxid under nitrogenatmosfære, medens temperaturen blev holdt på 20-25°C. Blandingen blev omrørt .i 10 minutter, og en opløsning af 0,715 g methylisothiocyanat i 3 ml dimethylsulfoxid (indeholdende 7,5% vand) blev tildryppet i løbet 25 af 2 minutter. Omrøringen blev fortsat i 1/2 time ved stuetemperatur, hvorefter 1,52 g methyliodid blev tildryppet i løbet af 2 minutter, medens temperaturen blev holdt på 20-25°C. Opløsningen blev omrørt ved stuetemperatur i 2 timer, fortyndet med 100 ml vand og oparbejdet på den i eksempel 1 30 i) beskrevne måde, hvorved man fik 0,96 g af titelforbindelsen (66,1%), smeltepunkt 113-115,5°C. ’ iv) Ved at gå frem som beskrevet i eksempel 1 iii), men s erstatte kalium-tert.butoxid med 1,6 g natriumhydroxid, gav 2,44 g nitromethan i 35 ml dimethylsulfoxid (indeholdende 35 7,5% vand) og 2,92 g methylisothiocyanat i 5 ml dimethylsulf- DK 170067 B1 7 oxid (indeholdende 7,5% vand) efterfulgt af alkylering med 6,25 g methyliodid 2,64 g af titelforbindelsen (44,5%), smeltepunkt 113-116°C.iii) 0.62 g of nitromethane was dropped over 2 minutes to a suspension of 1.1 g of potassium tert.butoxide in 9 ml of dry dimethyl sulfoxide under nitrogen atmosphere while maintaining the temperature of 20-25 ° C. The mixture was stirred for 10 minutes and a solution of 0.715 g of methyl isothiocyanate in 3 ml of dimethyl sulfoxide (containing 7.5% water) was added dropwise over 25 minutes. Stirring was continued for 1/2 hour at room temperature, after which 1.52 g of methyl iodide was added dropwise over 2 minutes while maintaining the temperature of 20-25 ° C. The solution was stirred at room temperature for 2 hours, diluted with 100 ml of water and worked up in the manner described in Example 1 (i) to give 0.96 g of the title compound (66.1%), mp 113-115.5 ° C. iv) By proceeding as described in Example 1 iii) but replacing potassium tert.butoxide with 1.6 g of sodium hydroxide gave 2.44 g of nitromethane in 35 ml of dimethyl sulfoxide (containing 35 7.5% water) and 2.92 g of methyl isothiocyanate in 5 ml of dimethyl sulfide oxide (containing 7.5% water) followed by alkylation with 6.25 g of methyl iodide 2.64 g of the title compound (44.5%), mp 113-116 ° C.
EKSEMPEL 2 5 N-Methyl-l-methylthio-2-nitroethenamin 20,88 g kaliumhydroxid i 12,4 ml vand blev sat til en omrørt opløsning af 27,22 g methylisothiocyanat og 22,75 g nitrome-than i 185 ml dimethylsulfoxid, medens temperaturen blev holdt på 10-15°C. Omrøring blev fortsat i 60 minutter ved ΙΟΙ 0 15°C, hvorefter opløsningen blev delt i to lige store portio ner på hver 120 ml.EXAMPLE 2 N-Methyl-1-methylthio-2-nitroethenamine 20.88 g of potassium hydroxide in 12.4 ml of water was added to a stirred solution of 27.22 g of methyl isothiocyanate and 22.75 g of nitromethane in 185 ml of dimethyl sulfoxide. while maintaining the temperature of 10-15 ° C. Stirring was continued for 60 minutes at 15 0 15 ° C, after which the solution was divided into two equal portions of 120 ml each.
i) Den første portion blev omrørt ved 10-15°C, medens 17,62 ml dimethylsulfat blev tilsat i løbet af 15 minutter. Omrøring blev fortsat i 30 minutter, hvorefter 90 ml vand blev 15 tilsat og blandingen oparbejdet på den i eksempel 1 i) beskrevne måde, hvorved man fik 12,45 g af titelforbindelsen (45,1%), smeltepunkt 112,5-114°C.i) The first portion was stirred at 10-15 ° C while 17.62 ml of dimethyl sulfate was added over 15 minutes. Stirring was continued for 30 minutes, then 90 ml of water was added and the mixture worked up in the manner described in Example 1 i) to give 12.45 g of the title compound (45.1%), mp 112.5-114 ° C.
ii) Den anden portion blev behandlet med 11,66 ml methyliodid og oparbejdet på samme måde, hvorved man fik 14,61 g af 20 titelforbindelsen (52,9%), smeltepunkt 112,5-114°C.ii) The second portion was treated with 11.66 ml of methyl iodide and worked up in the same manner to give 14.61 g of the title compound (52.9%), mp 112.5-114 ° C.
EKSEMPEL 3 N-Methyl-1-methylthio-2-nitroethenamin 1,05 g nitromethan og 1,26 g methylisothiocyanat i 6,71 g tørt dimethylsulfoxid blev i løbet af 70 minutter sat til en 25 omrørt suspension af 0,41 g natriumhydrid i 4,3 ml dimethyl-formamid, medens temperaturen blev holdt på under 25°C.EXAMPLE 3 N-Methyl-1-methylthio-2-nitroethenamine 1.05 g of nitromethane and 1.26 g of methyl isothiocyanate in 6.71 g of dry dimethyl sulfoxide were added over 70 minutes to a stirred suspension of 0.41 g of sodium hydride in 4.3 ml of dimethylformamide while maintaining the temperature below 25 ° C.
Omrøring blev fortsat i 3 timer, hvorefter 2,45 g methyliodid blev tilsat i løbet af 15 minutter, medens temperaturen blev holdt på under 30°C. Den resulterende opløsning blev omrørt i 30 30 minutter, 9 ml vand blev tilsat, og opløsningen blev DK 170067 Bl 8 oparbejdet på den i eksempel 1 i) beskrevne måde, hvorved man fik 1,30 g af titelforbindelsen (50,8%), smeltepunkt 113,5-115,5°C.Stirring was continued for 3 hours, after which 2.45 g of methyl iodide was added over 15 minutes while maintaining the temperature below 30 ° C. The resulting solution was stirred for 30 minutes, 9 ml of water was added and the solution worked up in the manner described in Example 1 i) to give 1.30 g of the title compound (50.8%). mp 113.5-115.5 ° C.
EKSEMPEL 4 5 N-Methyl-1-methylthio-2-nitroethenamin % 22,7 g nitromethan blev i løbet af 8 minutter sat til en omrørt suspension af 20,86 g kaliumhydroxid flager i 157,5 ml dimethylsulfoxid og 6,4 ml vand, medens temperaturen blev holdt på 15-20°C. En opløsning af 27,19 g methylisothiocyanat 10 i 27 ml dimethylsulfoxid og 1 ml vand blev tildryppet i løbet af 20 minutter, medens temperaturen blev holdt på 15-25°C.EXAMPLE 4 N-Methyl-1-methylthio-2-nitroethenamine% 22.7 g of nitromethane was added over 8 minutes to a stirred suspension of 20.86 g of potassium hydroxide flakes in 157.5 ml of dimethyl sulfoxide and 6.4 ml of water while maintaining the temperature of 15-20 ° C. A solution of 27.19 g of methyl isothiocyanate 10 in 27 ml of dimethyl sulfoxide and 1 ml of water was added dropwise over 20 minutes while maintaining the temperature of 15-25 ° C.
Omrøringen blev fortsat i yderligere 1 time ved stuetemperatur og 52,78 g methyliodid blev tilsat i løbet af 10 minutter, medens temperaturen blev holdt på 15-20°C. Den resulte-15 rende blanding blev omrørt i yderligere 1 time ved stuetemperatur, hvorefter 178 ml vand blev tilsat og blandingen oparbejdet på den i eksempel 1 i) beskrevne måde, hvorved man fik 25,68 g af titelforbindelsen (46,6%), smeltepunkt 113-116°C.Stirring was continued for an additional hour at room temperature and 52.78 g of methyl iodide was added over 10 minutes while maintaining the temperature of 15-20 ° C. The resulting mixture was stirred for an additional hour at room temperature, after which 178 ml of water was added and the mixture worked up in the manner described in Example 1 i) to give 25.68 g of the title compound (46.6%). mp 113-116 ° C.
20 EKSEMPEL 5 N-[2-[5-(Dimethylamino)methyl-2-furanylmethylthioJ ethyl]-N'-methyl-2-nitro-1,1-ethendiaminEXAMPLE 5 N- [2- [5- (Dimethylamino) methyl-2-furanylmethylthio] ethyl] -N'-methyl-2-nitro-1,1-ethylenediamine
En opløsning af 32,1 g 2-[5-(N,N-dimethylaminomethyl)-2-furanmethylthio]ethylamin i 25 ml vand blev i løbet åf 4 25 timer dryppet til en omrørt opløsning af 23 g N-methyl-1- methylthio-2-nitroethenamin i 40 ml vand ved 50°C. Reaktionsblandingen blev opvarmet til 50°C i yderligere 2 timer og , derpå opvarmet til 90°C. 150 ml methylisobutylketon blev sat til opløsningen, og vandet blev fjernet ved azeotrop destil-30 lation. Opløsningen blev afkølet til 60° C og 1,5 g aktivt kul tilsat. Blandingen blev filtreret, aktivkulremanensen vasket med 50 ml methylisobutylketon og de samlede filtrater ogA solution of 32.1 g of 2- [5- (N, N-dimethylaminomethyl) -2-furan methylthio] ethylamine in 25 ml of water was dropped over a period of 4 hours to a stirred solution of 23 g of N-methyl-1 methylthio-2-nitroethenamine in 40 ml of water at 50 ° C. The reaction mixture was heated to 50 ° C for an additional 2 hours and then heated to 90 ° C. 150 ml of methyl isobutyl ketone was added to the solution and the water was removed by azeotropic distillation. The solution was cooled to 60 ° C and 1.5 g of activated carbon was added. The mixture was filtered, the activated carbon residue washed with 50 ml of methyl isobutyl ketone and the combined filtrates and
Claims (7)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8415254 | 1984-06-15 | ||
| GB848415254A GB8415254D0 (en) | 1984-06-15 | 1984-06-15 | Amine derivatives |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK270585D0 DK270585D0 (en) | 1985-06-14 |
| DK270585A DK270585A (en) | 1985-12-16 |
| DK170067B1 true DK170067B1 (en) | 1995-05-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| DK270585A DK170067B1 (en) | 1984-06-15 | 1985-06-14 | Process for the preparation of amine derivatives |
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| Country | Link |
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| JP (2) | JPH0643382B2 (en) |
| KR (1) | KR870002019B1 (en) |
| AT (1) | AT395974B (en) |
| BE (1) | BE902655A (en) |
| CA (1) | CA1256454A (en) |
| CH (1) | CH667871A5 (en) |
| DE (1) | DE3521456A1 (en) |
| DK (1) | DK170067B1 (en) |
| ES (1) | ES8705359A1 (en) |
| FI (1) | FI82239C (en) |
| FR (1) | FR2565972B1 (en) |
| GB (2) | GB8415254D0 (en) |
| HU (1) | HU198179B (en) |
| IE (1) | IE58606B1 (en) |
| IL (1) | IL75523A (en) |
| IT (1) | IT1209960B (en) |
| NL (1) | NL8501727A (en) |
| NO (1) | NO162461C (en) |
| PT (1) | PT80643B (en) |
| SE (1) | SE462913B (en) |
| SG (1) | SG92590G (en) |
| ZA (1) | ZA854502B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8907700D0 (en) * | 1989-04-05 | 1989-05-17 | Fine Organics Ltd | Preparation of substituted ethenes |
| EP0396830B1 (en) * | 1989-05-10 | 1993-10-27 | Council of Scientific and Industrial Research | An improved process for the preparation of 1-substituted amino-1-substituted thio-2-nitro alkenes |
| US5686588A (en) * | 1995-08-16 | 1997-11-11 | Yoo; Seo Hong | Amine acid salt compounds and process for the production thereof |
| YU52598A (en) * | 1998-11-19 | 2001-05-28 | D.D. Zdravlje- sektor za istraživanje i razvoj | Procedure for synthesis of n-[2[[[5-[ (dialkylamino)methyl] -2-furanil]methyl]thi0]etyl]-n'-alkyl-2-nitro 1,1 alkendiamine and its hydrochloride |
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| GB1421792A (en) * | 1973-05-17 | 1976-01-21 | Smith Kline French Lab | Heterocyclic substituted-1, 1-diamino-ethylene derivatives methods for their preparation and compositions containing them |
| GB1554153A (en) * | 1975-05-15 | 1979-10-17 | Smith Kline French Lab | Process for making 2-amino-2-alkylthionitroethylenes |
| GB1565966A (en) | 1976-08-04 | 1980-04-23 | Allen & Hanburys Ltd | Aminoalkyl furan derivatives |
-
1984
- 1984-06-15 GB GB848415254A patent/GB8415254D0/en active Pending
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1985
- 1985-06-13 IT IT8548213A patent/IT1209960B/en active
- 1985-06-14 SE SE8502973A patent/SE462913B/en not_active IP Right Cessation
- 1985-06-14 DK DK270585A patent/DK170067B1/en not_active IP Right Cessation
- 1985-06-14 AT AT0178085A patent/AT395974B/en active
- 1985-06-14 ES ES544214A patent/ES8705359A1/en not_active Expired
- 1985-06-14 KR KR1019850004197A patent/KR870002019B1/en not_active IP Right Cessation
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- 1985-06-14 IL IL75523A patent/IL75523A/en not_active IP Right Cessation
- 1985-06-14 PT PT80643A patent/PT80643B/en not_active IP Right Cessation
- 1985-06-14 HU HU852367A patent/HU198179B/en not_active IP Right Cessation
- 1985-06-14 GB GB08515195A patent/GB2160204B/en not_active Expired
- 1985-06-14 ZA ZA854502A patent/ZA854502B/en unknown
- 1985-06-14 DE DE19853521456 patent/DE3521456A1/en active Granted
- 1985-06-14 FR FR858509049A patent/FR2565972B1/en not_active Expired
- 1985-06-14 CH CH2530/85A patent/CH667871A5/en not_active IP Right Cessation
- 1985-06-14 BE BE0/215184A patent/BE902655A/en not_active IP Right Cessation
- 1985-06-15 JP JP60130673A patent/JPH0643382B2/en not_active Expired - Fee Related
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1990
- 1990-11-13 SG SG925/90A patent/SG92590G/en unknown
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1993
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