CA1256454A - Preparation of amine derivatives - Google Patents
Preparation of amine derivativesInfo
- Publication number
- CA1256454A CA1256454A CA000484041A CA484041A CA1256454A CA 1256454 A CA1256454 A CA 1256454A CA 000484041 A CA000484041 A CA 000484041A CA 484041 A CA484041 A CA 484041A CA 1256454 A CA1256454 A CA 1256454A
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- Prior art keywords
- methyl
- formula
- compound
- nitromethane
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Furan Compounds (AREA)
- Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Electromechanical Clocks (AREA)
Abstract
A B S T R A C T
PREPARATION of Amine Derivatives Compounds of formula (II) (II) in which R1 is C1-4 alkyl, preferably methyl, are prepared by reaction of a compound of formula (I) (I) where Q is hydrogen or a cation derived from a suitable base with a suitable alkylating agent such as an alkyl halide or a dialkyl sulphate. The compound of formula (II) may be converted into a histamine H2-antagonist containing an -NHC(=CHNO2)NHCH3 end group, e.g. ranitidine by reaction with an appropriate amine.
The compound of formula (I) may be prepared by reaction of methyl isothiocyanate with the carbanion of nitromethane (preferably generated in situ by reaction of nitromethane with a suitable base) in the presence of dimethyl sulphoxide as solvent, Q representing the cation derived from the base used to produce the carbanion of nitromethane.
PREPARATION of Amine Derivatives Compounds of formula (II) (II) in which R1 is C1-4 alkyl, preferably methyl, are prepared by reaction of a compound of formula (I) (I) where Q is hydrogen or a cation derived from a suitable base with a suitable alkylating agent such as an alkyl halide or a dialkyl sulphate. The compound of formula (II) may be converted into a histamine H2-antagonist containing an -NHC(=CHNO2)NHCH3 end group, e.g. ranitidine by reaction with an appropriate amine.
The compound of formula (I) may be prepared by reaction of methyl isothiocyanate with the carbanion of nitromethane (preferably generated in situ by reaction of nitromethane with a suitable base) in the presence of dimethyl sulphoxide as solvent, Q representing the cation derived from the base used to produce the carbanion of nitromethane.
Description
` ~5~i~a?~j;
Preparation of Amine Derivatives The present inVentiGn relates to the pre-paration of amine derivatives. N-Methyl-l-alkylthio-2-nitroethenamine derivatives are useful as interrnediates for the preparation of ranitidine and other histamine H2-antagonists containing the -NHC(=CHN02)NHCH3 end group, such as nizatidine.
Such intermediates have previously been prepared by direct displacement of a single alkylthio group in 2,2-bisalkylthio-l-nitroethene derivatives by reaction with methylamine. However this reaction suffers from a lack of selectivity and provides N-methyl-l-alkylthio-2-nitroethenes contaminated with both unreacted starting material and the bis-aminated side product 2,2-bismethylamino-1-nitroethene.
British Patent Specification 1421792 discloses the preparation of compounds of formula R2S \ "
X / Y
in which X and Y, which may be the same or different, each represent hydrogen, nitro, cyano, or S02Ar (where Ar is optionally substituted phenyl) ? except that X and Y cannot both represent hydrogen, R represents lower alkyl and R2 .
$~
represents lower alkyl or ara]kyl, by the fol1owing reaction sequence:
CH XY C S> S ~ / NHR R2~]al \ C /
1 "
CHXY / C \
The substituted methane CH2XY is said to be reacted 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 which is disclosed, methyl isothiocyanate is reacted with rnalononitrile in the presence of sodium hydride and dimethylformamide. The second stage-of the reactlon is carried out by adding methyl iodide in dimethylformamide.
Chem. Ber.100 591-604(1967) discloses the reaction of - phenyl isothiocyanate with nitromethane and also discloses that the reaction should be carried out in the presence of sodium hydride in dimethylformamide. The reaction is followed by methylation with methyl iodide to produce N-phenyl-1-methylthio-2-nitroethenamine.
The use of sodium hydride in dimethylformamide as taught by the documents referred to above is unsuitable for large scale preparations in view of the known hazards 25 ~associated with the combination of these reagents.
~:5~45q~
The present invention pro~ides a process for the preparation of a compound of formula (I) QS
~C=CHN02 (I) which comprises reacting methyl isothiocyanate with the carbanion of nitromethane in the presence of dimethyl sul-phoxide as solvent, optionally in the presence of a co-solvent. The carbanion is conveniently generated in situ from nitromethane by reaction with a suitable base. In formula (I), Q represents a cation derived frorn the base used to prepare the carbanion of nitromethane.
The compound of formula (I) wherein Q is a hydrogen atom may be prepared from the compound of forrnula (I) in which Q is a cation by addition of one equivalent of a suitable acid.
The compound of formula (I) wherein Q is hydrogen or a cation may be treated with an appropriate alkylating agent such as an alkyl halide (e.g. methyl bromide or methyl iodide) or a dialkyl sulphate (e.g. dimethyl sulphate), to produce an N-methyl-l-alkylthio-2-nitro-ethenamine derivative of formula (II) RlS \
C=CHN02 (II) ~2~i~45~
1, wherein R1 is a C1 ~ alkyl group, preferably methyl.
It has now surprlsingly been f'ound that forrnation of the compound of formula (I) and thus production of the N-methyl-1-alkylthio-2-nitroethanarnine derivatives of formula (II) takes place in particularly good yield, provided that the reaction between methyl isothiocyanate and the carbanion of nitromethane is carried out in dimethyl sulphoxide as a solvent, optionally in the presence of a co-solvent. Thus when the reaction of methyl iso-thiocyanate with nitromethane is carried out in the presenceof sodium hydride as base the yield increases from 22% when dimethylformamide is used as solvent to 59% when dimethyl sulphoxide is used as solvent.
Preferably thé compound of formula (I) is reacted in situ with the alkylating agent and in this case the reaction will also generally be carried out in the same solvent medium.
A preferred process according to the invention for preparing N-methyl-1-alkylthio-2-nitroethenamine derivatives of formula (II) comprises reacting methyl isothiocyanate with the carbanion of nitromethane to give the compound of formula (I) in situ followed by alkylation with an appropriate alkylating agent as referred to above, the reaction being carried out in the presence of dimethyl sulphoxide as solvent, optionally in the presence of a co-solvent. Suitable co-solvents, the choice of which depends on the base used, include aprotic sol.vents (such as dimethylformamide and N-'a5~
.
methylpyrrolldinone) and water.
A particular ernbodirnent of this process involvesmethylation of the compound Or forrnula (I) prepared in situ using a suitable methylatin~ agent such as methyl iodide or dimethyl sulphate to give N-methyl-l-rnethylthio-2-nitro-ethenamine, i.e. the compound of formula (II) where R1 is methyl.
The compounds of formula (I) are novel. They can exist in tautomeric forms and formula (I) is intended to include all such forms. Compounds of formula (I) in which Q repre-sents hydrogen or an alkali metal cation (particularly sodiumor potassium) represent a further aspect of the invention.
The process of the present invention gives N~methyl-1-alkylthio-2-nitroethenamines of formula (II) in good yield and in a form that may be used to prepare compounds such as ranitidine without further purification. This, process, which uses cheap simple and commercially available starting materials, may in general be carried out safely on a large scale and under mild conditions. The process of the invention is particularly applicable to the preparation of . ~ .
N-methyl-1-methylthio-2~nitroethenamine.
Convenlently the carbanion of nitromethane is prepareq in situ by treating nitromethane with a suitable base.
Particularly suitable bases include alkali metal hydrides, alkali metal hydroxides or alkali metal alkoxides, for example sodium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium isopropoxide and potassium tert~
butoxide. Alkali metal hydroxides are pre~erred and when the base is an alkali r.letal hydroxide it may~e added as an aqueous soluti~on.
`~ ~256~5~
~6--Where subsequent reaction with the alkylating agent is carried out on the compound of formula (I~ prepared in situ then the same solvent rnedium will generally be used for the alkylation reaction.
The temperature of the reaction is conveniently within the range 0-50C, and the reaction is preferably carried out at room temperature.
According to a further aspect, the invention provides a process for the preparation of compounds, particularly histamine H2 antagonists, containing an -NHC(=CHN02)NHCH3 end group which comprises reacting an N-methyl-1-alkylthio-2-nitroethenamine derivative of formula (II), prepared as described above, with an appropriate amine. Thus, in accordance with this aspect of the invention, ranitidine may be prepared from 2-[5-(N,N-dir.~ethylaminomethyl)-2-furanmethylthi.o]ethylamine as the amine, . preferably using N-methyl-1-methylthio-2-nitroethenamine as the~compound of formula (II). The reaction may be carried out in a solvent such as water, optionally with heating.
The invention is illustrated but in no way limited by the following Examples:
~25~
Example l N-Methyl-l-methylthio-2-nitroethenamine .
5 (i) Nitromethane (1.259) was added over l min. to a suspension of flake potassium hydroxide (1.159) in di-methyl sulphoxide (containing 7.5~ water) (l~lml). A
solution of methyl isothiocyanate (1.59) in dimethyl sulphoxide (containing 7.5~ water) (2.5ml) was added over lO 2 min. keeping the temperature at 20-26. The solution was stirred for a further û.5h at room temperature and methyl iodide (3.199) was added dropwise over 2 rnin.
keeping the tèmperature at 22-24. Stirring was continued for lh. at room temperature, and the solution was then 15 diluted with water (200ml) and extracted with dichloromethane. The combined extracts were washed with water, evaporated to dryness, and the residue was crystallised from 2-propanol to give the title compound (1.59), Y49.4' m.p. 113-116.5.
(ii) Nitromethane (1.329) in dimethyl sulphoxide (containing 7.5~ water) (5ml) was added over 5 min. at 0-5 to sodium hydride (0.529) in dimethyl sulphoxide (containing 7.50 water)(20ml). The rnixture was allowed to 25 warm to room temperature and after a further 30 min.
methyl isothiocyanate (1.5~39) in dimethyl sulphoxide (containing 7.5~ water) (5ml) was added over 5 min.
~25645a~
The mixture was treated with methyl iodide ~3.07~) in dimethyl sulphoxide (containing 7.5Vo water) (5ml) keeping the temperature below 30, and the resulting solution was stirred overnight. The solvent was rernoved, water (50ml) was added to the residue and the mixture was worked up according to the procedure in Example l(i) to give the title compound (1.889), Y58.7~. m.p. 112-114~.
(iii) Nitromethane (0.629) was added dropwise over 2 min. to a suspension of potassium tert-butoxide (1.19) in dry dimethyl sulphoxide (9m1) under an atmosphere of nitrogen with the temperature kept at 20-25. The mixture was stirred for 10 min. and a solution of methyl 15 isothiocyanate (0.7159) in dimethyl sulphoxide (containing 7.5~ water) (3ml) was added dropwise over 2 min. Stirring was continued for 0.5h at room temperature and then methyl iodide (1.529) was added dropwise over 2 minO with the temperature kept at 20-25. The solution was s~tirred at room temperature for 2h., diluted with wnter (InOml) Mnd worked up according to the procedure in Example l(i) to give the title compound (0.96g),Y66.1V. m.p. 113-115.5.
S~
(iv) According to the procedure in Exarnple l(iii), but replacing potassium tert-butoxide with sodium hydrbxide (1.6q), nitromethane (2.449) in dimethyl sulphoxide (containing 7.50 water) (35ml) and methyl isothiocyanate (2.929) in dimethyl sulphoxide (containing 7.5~ water) (5ml) followed by alkylation with methyl iodide (6.259) gave the title compound (2.64q), Y44.5~. m.p. 113-116.
Example 2 N-Methyl-l-methylthio-2-nitroethenamine Potassium hydroxide (20,889) in water (12.4ml) was added to a stirred solution of methyl isothiocyanate (27.229) and nitromethane (22.759) in dimethyl sulphoxide (185ml), keeping the temperature at 10-15. Stirring was continued for 60 min. at 10-15 then the solution was divided into 2 equal portions (each 120ml).
(i) The first portion was stirred at 10-15 while dimethyl sulphate (17.62ml) was added over 15 min. Stirring was continued for 30 min, then water (9Oml) was added and the mixture was worked up according to the procedure in Example l(i) to give the title compound (12.45q), Y4501~.
m.p. 112.5 - 114.
' ~2~
(ii) The second portion was treated with methyl iodide (11.66ml) and worked up in the snme manner to give the - title compound (14.619), Y52.9~. m.p. 112.5 - 114.
Exsmple 3 N-Methyl-l-methylthio-2-nitroethenamine -Nitromethane (1.05q) and methyl isothiocyanate (1.269) in dry dimethyl sulphoxide t6.71g) was added over 70 min. to a stirred suspension of sodium hydride (0.419) in dimethylformamide (4.3ml) with the temperature kept below 25. Stirring WflS continued for 3h. then methyl iodide (2.459) was sdded over 15 min. keeping the temperature below 30. The resulting solution was stirred for 30 min., water (9ml) was added and the solution was worked up according to the procedure in Example l(i) to give the title compound. (1.30g),Y50.8~. m.p. 113.5-115.5.
Example 4 N-Methyl-l-methylthio-2-nitroethenamine Nitromethane (22.79) w~s added over 8 min. to a stirred suspension of flake potsssium hydroxide (20~869) in ' `
~256a~5~
dimethyl sulphoxide (157.5ml) and water (6.~ml) keeping the temperature at 15-20. A solution of methyl isothiocyanate (27.199) in dirnethyl sulphoxide (27rnl) and water (lml) was added dropwise over 20 min. keeping the temperature at 15-25. Stirring was cc,ntinued for a further lh. at room temperature and methyl iodide (52.789) was added over 10 min. keeping the temperature at 15-20.
The resulting mixture was stirred for a further lh. at room temperature then water (178ml) was added and the mixture was worked up according to the procedure in Example 1 (i) to give the title compound (25.689), Y46.6~.
m.p .113-116.
Example 5 N-[2-[5-(Dimethylamino)methyl-2-furanylmethylthio]ethyl]-N'-methyl-2-nitro-1,1-ethenediarnine A solution of 2-[5-(N9N-dimethylaminomethyl)-2-furan-methylthio]ethylamine (32.19) in water (25ml) was added dropwise over 4h. to a stirred solution of N-methyl-1-methylthio-2-nitroethenamine (239) in water (4ûml) at 50.
The reaction mixture was heated at 50 for a further 2h.
and then heated to 90. Methyl isobutyl ketone (150ml) WflS ad'ded to the solution and the wflter removed by azeotropic distilla'tion. The solution was cooled at 60 .
~ ~;25i454 `` -12 and charcoal (1.59) added. The mixture was filtered, the charcoal residue washed with rnethyl isobutyl ketone (5OM1) and the cornbined Filtrate and wash;ng~, were cooled to 0.
The title compound (~99) rn.p.6~-70 crystallised and was filtered off.
Preparation of Amine Derivatives The present inVentiGn relates to the pre-paration of amine derivatives. N-Methyl-l-alkylthio-2-nitroethenamine derivatives are useful as interrnediates for the preparation of ranitidine and other histamine H2-antagonists containing the -NHC(=CHN02)NHCH3 end group, such as nizatidine.
Such intermediates have previously been prepared by direct displacement of a single alkylthio group in 2,2-bisalkylthio-l-nitroethene derivatives by reaction with methylamine. However this reaction suffers from a lack of selectivity and provides N-methyl-l-alkylthio-2-nitroethenes contaminated with both unreacted starting material and the bis-aminated side product 2,2-bismethylamino-1-nitroethene.
British Patent Specification 1421792 discloses the preparation of compounds of formula R2S \ "
X / Y
in which X and Y, which may be the same or different, each represent hydrogen, nitro, cyano, or S02Ar (where Ar is optionally substituted phenyl) ? except that X and Y cannot both represent hydrogen, R represents lower alkyl and R2 .
$~
represents lower alkyl or ara]kyl, by the fol1owing reaction sequence:
CH XY C S> S ~ / NHR R2~]al \ C /
1 "
CHXY / C \
The substituted methane CH2XY is said to be reacted 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 which is disclosed, methyl isothiocyanate is reacted with rnalononitrile in the presence of sodium hydride and dimethylformamide. The second stage-of the reactlon is carried out by adding methyl iodide in dimethylformamide.
Chem. Ber.100 591-604(1967) discloses the reaction of - phenyl isothiocyanate with nitromethane and also discloses that the reaction should be carried out in the presence of sodium hydride in dimethylformamide. The reaction is followed by methylation with methyl iodide to produce N-phenyl-1-methylthio-2-nitroethenamine.
The use of sodium hydride in dimethylformamide as taught by the documents referred to above is unsuitable for large scale preparations in view of the known hazards 25 ~associated with the combination of these reagents.
~:5~45q~
The present invention pro~ides a process for the preparation of a compound of formula (I) QS
~C=CHN02 (I) which comprises reacting methyl isothiocyanate with the carbanion of nitromethane in the presence of dimethyl sul-phoxide as solvent, optionally in the presence of a co-solvent. The carbanion is conveniently generated in situ from nitromethane by reaction with a suitable base. In formula (I), Q represents a cation derived frorn the base used to prepare the carbanion of nitromethane.
The compound of formula (I) wherein Q is a hydrogen atom may be prepared from the compound of forrnula (I) in which Q is a cation by addition of one equivalent of a suitable acid.
The compound of formula (I) wherein Q is hydrogen or a cation may be treated with an appropriate alkylating agent such as an alkyl halide (e.g. methyl bromide or methyl iodide) or a dialkyl sulphate (e.g. dimethyl sulphate), to produce an N-methyl-l-alkylthio-2-nitro-ethenamine derivative of formula (II) RlS \
C=CHN02 (II) ~2~i~45~
1, wherein R1 is a C1 ~ alkyl group, preferably methyl.
It has now surprlsingly been f'ound that forrnation of the compound of formula (I) and thus production of the N-methyl-1-alkylthio-2-nitroethanarnine derivatives of formula (II) takes place in particularly good yield, provided that the reaction between methyl isothiocyanate and the carbanion of nitromethane is carried out in dimethyl sulphoxide as a solvent, optionally in the presence of a co-solvent. Thus when the reaction of methyl iso-thiocyanate with nitromethane is carried out in the presenceof sodium hydride as base the yield increases from 22% when dimethylformamide is used as solvent to 59% when dimethyl sulphoxide is used as solvent.
Preferably thé compound of formula (I) is reacted in situ with the alkylating agent and in this case the reaction will also generally be carried out in the same solvent medium.
A preferred process according to the invention for preparing N-methyl-1-alkylthio-2-nitroethenamine derivatives of formula (II) comprises reacting methyl isothiocyanate with the carbanion of nitromethane to give the compound of formula (I) in situ followed by alkylation with an appropriate alkylating agent as referred to above, the reaction being carried out in the presence of dimethyl sulphoxide as solvent, optionally in the presence of a co-solvent. Suitable co-solvents, the choice of which depends on the base used, include aprotic sol.vents (such as dimethylformamide and N-'a5~
.
methylpyrrolldinone) and water.
A particular ernbodirnent of this process involvesmethylation of the compound Or forrnula (I) prepared in situ using a suitable methylatin~ agent such as methyl iodide or dimethyl sulphate to give N-methyl-l-rnethylthio-2-nitro-ethenamine, i.e. the compound of formula (II) where R1 is methyl.
The compounds of formula (I) are novel. They can exist in tautomeric forms and formula (I) is intended to include all such forms. Compounds of formula (I) in which Q repre-sents hydrogen or an alkali metal cation (particularly sodiumor potassium) represent a further aspect of the invention.
The process of the present invention gives N~methyl-1-alkylthio-2-nitroethenamines of formula (II) in good yield and in a form that may be used to prepare compounds such as ranitidine without further purification. This, process, which uses cheap simple and commercially available starting materials, may in general be carried out safely on a large scale and under mild conditions. The process of the invention is particularly applicable to the preparation of . ~ .
N-methyl-1-methylthio-2~nitroethenamine.
Convenlently the carbanion of nitromethane is prepareq in situ by treating nitromethane with a suitable base.
Particularly suitable bases include alkali metal hydrides, alkali metal hydroxides or alkali metal alkoxides, for example sodium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium isopropoxide and potassium tert~
butoxide. Alkali metal hydroxides are pre~erred and when the base is an alkali r.letal hydroxide it may~e added as an aqueous soluti~on.
`~ ~256~5~
~6--Where subsequent reaction with the alkylating agent is carried out on the compound of formula (I~ prepared in situ then the same solvent rnedium will generally be used for the alkylation reaction.
The temperature of the reaction is conveniently within the range 0-50C, and the reaction is preferably carried out at room temperature.
According to a further aspect, the invention provides a process for the preparation of compounds, particularly histamine H2 antagonists, containing an -NHC(=CHN02)NHCH3 end group which comprises reacting an N-methyl-1-alkylthio-2-nitroethenamine derivative of formula (II), prepared as described above, with an appropriate amine. Thus, in accordance with this aspect of the invention, ranitidine may be prepared from 2-[5-(N,N-dir.~ethylaminomethyl)-2-furanmethylthi.o]ethylamine as the amine, . preferably using N-methyl-1-methylthio-2-nitroethenamine as the~compound of formula (II). The reaction may be carried out in a solvent such as water, optionally with heating.
The invention is illustrated but in no way limited by the following Examples:
~25~
Example l N-Methyl-l-methylthio-2-nitroethenamine .
5 (i) Nitromethane (1.259) was added over l min. to a suspension of flake potassium hydroxide (1.159) in di-methyl sulphoxide (containing 7.5~ water) (l~lml). A
solution of methyl isothiocyanate (1.59) in dimethyl sulphoxide (containing 7.5~ water) (2.5ml) was added over lO 2 min. keeping the temperature at 20-26. The solution was stirred for a further û.5h at room temperature and methyl iodide (3.199) was added dropwise over 2 rnin.
keeping the tèmperature at 22-24. Stirring was continued for lh. at room temperature, and the solution was then 15 diluted with water (200ml) and extracted with dichloromethane. The combined extracts were washed with water, evaporated to dryness, and the residue was crystallised from 2-propanol to give the title compound (1.59), Y49.4' m.p. 113-116.5.
(ii) Nitromethane (1.329) in dimethyl sulphoxide (containing 7.5~ water) (5ml) was added over 5 min. at 0-5 to sodium hydride (0.529) in dimethyl sulphoxide (containing 7.50 water)(20ml). The rnixture was allowed to 25 warm to room temperature and after a further 30 min.
methyl isothiocyanate (1.5~39) in dimethyl sulphoxide (containing 7.5~ water) (5ml) was added over 5 min.
~25645a~
The mixture was treated with methyl iodide ~3.07~) in dimethyl sulphoxide (containing 7.5Vo water) (5ml) keeping the temperature below 30, and the resulting solution was stirred overnight. The solvent was rernoved, water (50ml) was added to the residue and the mixture was worked up according to the procedure in Example l(i) to give the title compound (1.889), Y58.7~. m.p. 112-114~.
(iii) Nitromethane (0.629) was added dropwise over 2 min. to a suspension of potassium tert-butoxide (1.19) in dry dimethyl sulphoxide (9m1) under an atmosphere of nitrogen with the temperature kept at 20-25. The mixture was stirred for 10 min. and a solution of methyl 15 isothiocyanate (0.7159) in dimethyl sulphoxide (containing 7.5~ water) (3ml) was added dropwise over 2 min. Stirring was continued for 0.5h at room temperature and then methyl iodide (1.529) was added dropwise over 2 minO with the temperature kept at 20-25. The solution was s~tirred at room temperature for 2h., diluted with wnter (InOml) Mnd worked up according to the procedure in Example l(i) to give the title compound (0.96g),Y66.1V. m.p. 113-115.5.
S~
(iv) According to the procedure in Exarnple l(iii), but replacing potassium tert-butoxide with sodium hydrbxide (1.6q), nitromethane (2.449) in dimethyl sulphoxide (containing 7.50 water) (35ml) and methyl isothiocyanate (2.929) in dimethyl sulphoxide (containing 7.5~ water) (5ml) followed by alkylation with methyl iodide (6.259) gave the title compound (2.64q), Y44.5~. m.p. 113-116.
Example 2 N-Methyl-l-methylthio-2-nitroethenamine Potassium hydroxide (20,889) in water (12.4ml) was added to a stirred solution of methyl isothiocyanate (27.229) and nitromethane (22.759) in dimethyl sulphoxide (185ml), keeping the temperature at 10-15. Stirring was continued for 60 min. at 10-15 then the solution was divided into 2 equal portions (each 120ml).
(i) The first portion was stirred at 10-15 while dimethyl sulphate (17.62ml) was added over 15 min. Stirring was continued for 30 min, then water (9Oml) was added and the mixture was worked up according to the procedure in Example l(i) to give the title compound (12.45q), Y4501~.
m.p. 112.5 - 114.
' ~2~
(ii) The second portion was treated with methyl iodide (11.66ml) and worked up in the snme manner to give the - title compound (14.619), Y52.9~. m.p. 112.5 - 114.
Exsmple 3 N-Methyl-l-methylthio-2-nitroethenamine -Nitromethane (1.05q) and methyl isothiocyanate (1.269) in dry dimethyl sulphoxide t6.71g) was added over 70 min. to a stirred suspension of sodium hydride (0.419) in dimethylformamide (4.3ml) with the temperature kept below 25. Stirring WflS continued for 3h. then methyl iodide (2.459) was sdded over 15 min. keeping the temperature below 30. The resulting solution was stirred for 30 min., water (9ml) was added and the solution was worked up according to the procedure in Example l(i) to give the title compound. (1.30g),Y50.8~. m.p. 113.5-115.5.
Example 4 N-Methyl-l-methylthio-2-nitroethenamine Nitromethane (22.79) w~s added over 8 min. to a stirred suspension of flake potsssium hydroxide (20~869) in ' `
~256a~5~
dimethyl sulphoxide (157.5ml) and water (6.~ml) keeping the temperature at 15-20. A solution of methyl isothiocyanate (27.199) in dirnethyl sulphoxide (27rnl) and water (lml) was added dropwise over 20 min. keeping the temperature at 15-25. Stirring was cc,ntinued for a further lh. at room temperature and methyl iodide (52.789) was added over 10 min. keeping the temperature at 15-20.
The resulting mixture was stirred for a further lh. at room temperature then water (178ml) was added and the mixture was worked up according to the procedure in Example 1 (i) to give the title compound (25.689), Y46.6~.
m.p .113-116.
Example 5 N-[2-[5-(Dimethylamino)methyl-2-furanylmethylthio]ethyl]-N'-methyl-2-nitro-1,1-ethenediarnine A solution of 2-[5-(N9N-dimethylaminomethyl)-2-furan-methylthio]ethylamine (32.19) in water (25ml) was added dropwise over 4h. to a stirred solution of N-methyl-1-methylthio-2-nitroethenamine (239) in water (4ûml) at 50.
The reaction mixture was heated at 50 for a further 2h.
and then heated to 90. Methyl isobutyl ketone (150ml) WflS ad'ded to the solution and the wflter removed by azeotropic distilla'tion. The solution was cooled at 60 .
~ ~;25i454 `` -12 and charcoal (1.59) added. The mixture was filtered, the charcoal residue washed with rnethyl isobutyl ketone (5OM1) and the cornbined Filtrate and wash;ng~, were cooled to 0.
The title compound (~99) rn.p.6~-70 crystallised and was filtered off.
Claims (10)
1. A process for the preparation of an N-methyl-1-alkyl-thio-2-nitroethenamine derivative of the general formula (II).
(II) wherein R1 is a C1-4 alkyl group, which comprises:
(a) reacting a methyl isothiocyanate with the carbanion of nitromethane in the presence of dimethyl sulphoxide as solvent to produce a compound of the general formula (I) (I) wherein Q represents a cation derived from a suitable base used to generate the carbanion of nitromethane in situ; and (b) reacting the thus produced compound of the general formula (I) with a suitable alkylating agent to produce the N-methyl-l-alkylthio-2-nitroethenamines derivative of the general formula (II).
(II) wherein R1 is a C1-4 alkyl group, which comprises:
(a) reacting a methyl isothiocyanate with the carbanion of nitromethane in the presence of dimethyl sulphoxide as solvent to produce a compound of the general formula (I) (I) wherein Q represents a cation derived from a suitable base used to generate the carbanion of nitromethane in situ; and (b) reacting the thus produced compound of the general formula (I) with a suitable alkylating agent to produce the N-methyl-l-alkylthio-2-nitroethenamines derivative of the general formula (II).
2. A process as claimed in claim 1 wherein dimethyl sulphoxide is used together with co-solvent in step (a).
3. A process as claimed in claim 1 wherein the base of step (a) is an alkali metal hydroxide.
4. A process as claimed in claim 3 wherein the base is an alkali metal hydroxide used as an aqueous solution.
5. A process as claimed in claims 3 or 4 wherein the alkali metal hydroxide is potassium hydroxide.
6. A process as claimed in claim 1 wherein the base of step (a) is an alkali metal hydride or an alkali metal alkoxide.
7. A process as claimed in claim 6 wherein the base is sodium hydride or potassium tert-butoxide.
8. A process as claimed in claim 1 wherein the reaction with the alkylating agent in stept (b) is carried out on the compound of the formula (I) prepared in situ.
9. A process as claimed in claim 1 wherein the alkylating agent in step (b) is an alkyl halide or a dialkyl sulphate.
10. A process as claimed in claim 1 for the preparation of the compound of the formula (II) as defined in claim 1 in which R1 is methyl, wherein the alkylating agent in step (b) is methyl iodide or dimethyl sulphate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000590391A CA1308732C (en) | 1984-06-15 | 1989-02-07 | Preparation of amine derivatives |
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 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000590391A Division CA1308732C (en) | 1984-06-15 | 1989-02-07 | Preparation of amine derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1256454A true CA1256454A (en) | 1989-06-27 |
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ID=10562466
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000484041A Expired CA1256454A (en) | 1984-06-15 | 1985-06-14 | Preparation of amine derivatives |
Country Status (22)
| Country | Link |
|---|---|
| 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) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HU9203905D0 (en) * | 1989-04-05 | 1993-04-28 | Glaxo Group Ltd | Method for producing ranitidine |
| 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 DK DK270585A patent/DK170067B1/en not_active IP Right Cessation
- 1985-06-14 HU HU852367A patent/HU198179B/en not_active IP Right Cessation
- 1985-06-14 NO NO852418A patent/NO162461C/en not_active IP Right Cessation
- 1985-06-14 NL NL8501727A patent/NL8501727A/en not_active IP Right Cessation
- 1985-06-14 FI FI852366A patent/FI82239C/en active IP Right Grant
- 1985-06-14 ZA ZA854502A patent/ZA854502B/en unknown
- 1985-06-14 ES ES544214A patent/ES8705359A1/en not_active Expired
- 1985-06-14 KR KR1019850004197A patent/KR870002019B1/en not_active IP Right Cessation
- 1985-06-14 DE DE19853521456 patent/DE3521456A1/en active Granted
- 1985-06-14 AT AT0178085A patent/AT395974B/en active
- 1985-06-14 GB GB08515195A patent/GB2160204B/en not_active Expired
- 1985-06-14 IE IE148485A patent/IE58606B1/en not_active IP Right Cessation
- 1985-06-14 FR FR858509049A patent/FR2565972B1/en not_active Expired
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- 1985-06-14 CA CA000484041A patent/CA1256454A/en not_active Expired
- 1985-06-14 CH CH2530/85A patent/CH667871A5/en not_active IP Right Cessation
- 1985-06-14 PT PT80643A patent/PT80643B/en not_active IP Right Cessation
- 1985-06-14 SE SE8502973A patent/SE462913B/en not_active IP Right Cessation
- 1985-06-14 IL IL75523A patent/IL75523A/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
- 1993-09-16 JP JP5230589A patent/JPH06102656B2/en not_active Expired - Fee Related
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