CA1308732C - Preparation of amine derivatives - Google Patents

Abstract

A B S T R A C T

This invention relates to a process for the preparation of a compound containing an -NHC(=CHNO2)NHCH3. The process comprises reacting an N-methyl derviative of the general formula (II):

(II) wherein R1 is a C1-4 alkyl group, with a suitable amine.
The resulting compounds are useful histamine H2-antagonists.

Description

~ 3~J7~2 1 This is a divisional application of Canadian Patent ~pplication serial number 484,041 filed on June 14, 1985.
This invention relates to a process for the preparation of a compound containing an -NHC(=CHN02)NHCH3 end group which comprises reacting an N-methyl-l-alkylthio-2-nitroethenamine derivative of general formula (II) Rl C=CHN02 (II) wherein Rl is a Cl 4 alkyl group, with a suitable amine.
The present invention relates to the preparation of amine derivatives. N-Methyl-l-alkylthio-2-nitroethenamine derivatives are useful as intermediates 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 alkyl~hio 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 ~

.
.. :
.- .

1 7 .73~

1 bis-aminated side product 2,2-bismethylamino-1-nitroethene.
British Patent Specification 1421792 discloses the preparation of compounds of formula R2s NHR

., S ~C ~

in which X and Y, which may be the same or different, each represent hydrogen, nitro, cyano, or SOzAr (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 aralkyl, by the following reaction sequence:
R2s CH2XY RN=C=S~ ~ /NHR R2~al ~ C / NHR

1 ..
CHXY ~ C
:~ X ~y 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 malononitrile in the presence of sodium hydride and dimethylformamide. The second stage 2 ~ ~

t ~ 3 ~

1 of the reaction is carried our 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-l-methylthio-2-nitroethenamine.
The use of sodium hydride in dimethylformamide as taùght by the documents referred to above is unsuitable for large scale preparations in view of the known hazards associated with the combination of thege reagents.
To this end, in one of its aspects, the invention provides a process for the preparation of a compound containing an -NHC(=CHN02)NHCH3 end group which comprises reacting an N-methyl-l-alkylthio-2-nitroethenamine derivative of general formula (II) R l S
~ =CHNO2 (II) wherein Rl is a Cl 4 alkyl group, with a suitable amine.

~,.'? ~

1 7"in.73?~

The present invention provides a process for the preparation of a compound of formula (I) ~ C=CHN02 (I) CH3h'H ~

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 from the base used to prepare the carbanion of nitromethane.
Thé compound Or formula (I) wherein Q is a hydrogen atom may be prepared from the compound of formula (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 alkylatin~
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-1-alkylthio-2-nitro-ethenamine derivative of formula (II) .
R1S \
C=CHN02 (II) , .
..... ............... ......... ...... ... ............. ...... r ;~
' . . .
: . . ~ .,.
.

1 J ~i v 1 3 2 wherein Rl is a C1 4 alkyl group, preferably methyl.
It has now surprisingly been found that formation of the compound of formula (I) and thus production of the N-methyl-l-alkylthio-2-nitroethanamine 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 dimet~yl sulphoxide as a solvent, optional~y 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 (I1 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 gi~e 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 aprotfc solvents (such as dimethylformamide and N-.' ' ' ' , , .', ' ' ' , ~ , -- 1 7 ^ '\ -/ 7 ') ~J , ~ . I ~. . /

methylpyrrolidinone) and water.
A particular embodiment of this pr~cess involves methylation of the compound of formula (T) prepared in situ using a suitable methylating agent such as methyl iodide or dimethyl sulphate to give N-methyl-1-methylthio--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 ~ives 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 ranitldine w~thout further purlfication. ThLs, 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.
Conveniently the carbanion of nitromethane is prepared 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 hydroxlde, sodium ethoxide, sodium isopropoxide and potassium tert-butoxide. ~ ar~~~et~l hydroxi~has.~r¢çpEe~erreld ~nd~Yhen the ba8e-i~ ~n-alkali l~e*a~ h~ xoxid~ it ~ar ~e added ~ 4n j aqueou8 ~olut~on, 1 7 ~ 7 ~ ~
I J~ J~.

Where subsequent reaction with the alkylating agent ls carried out on the compound Or formuia (I) prepared in situ then the same solvent medium 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 frQm 2-[5-(N,N-dimethylaminomethyl)-2-furanmethylthio]ethylamine as the amine, preferably using N-methyl-1-methylthio-2-nitroethenaminé
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 limite.d by the following Examples:

s . .. .~
~: ' , . ' , ' ' ... . ....... .. .. ,., .. . .. , ... , ,__ _____ .

i 7 3 ~
.

Ex~mple 1 N-Methvl-l-methylthio-2-nitroethen~mine (i) Nitromethsne (1.259) W~8 added over 1 min. to a QuspensiOn of flake potassium hydroxide (1-159) in di-methyl sulphoxide (containing 7.5% water) (lBml). A
solution of methyli~othiocyanate (1.59) in dimethyl sulphoxide (containing 7.5Z water) (2.5ml) wa~,added over 2 min. keeping the tempersture At 20-26. The solution was stirred for a further 0.5h at room temperature and methyl iodide (3.199) sdded dropwise over 2 min. keeping the tempersture st 22-24. Stirrlng wss contlnued ~or lh.
st room t'empersture, end the ~olution wa~ then diluted wlth wate,r (200ml) snd extracted with dichloromethsne.
The combined extracts were washed with w~ter, evaporsted to dryness, and the residue was cryst~llised from 2-propsnol to give the title compound (1.5g), Y49.4Z m.p.
113-116.5.

(ii) Nitromethane (1.329) in dimethyl sulphoxid,e , (cont~ining 7.5Z water) (5ml) wa~ added over 5 mln. et 0-5 to sodium hydride (0.529) in dimet~yl sulphoxide (cnntaining 7.5~ w~ter (20ml). The mixture wa~ allowed to warm to room tempersture and ~fter ~ further ~0 m~n.
methyl isothiocyanate (1.589) in dimethyl sulphoxide ,(cont~lnlng 7.5Z wster) (5ml) ws~ ~dded over 5 min.
~, .

: : , 1 ~ ~, ,` 7 `, 2 The mixture wa~ treated with methyl iodide (3.079) in dimethyl sulpho%ide (containing 7.5~ weter) (5ml) keeping the temperature below 30, snd the resulting solution was stirred overnight. The solvent was removed, water (5ûml) wss added to the residue and the mixture was worked up according to the procedure in Example l(i) to qive the title compound (1.889), Y58.7Z. m.p. 112-114.

(iii) Nitromethane (û.62g) was edded dropwise over 2 min. to e suspension of potes~ium tert-butoxide (1.19) in dry dimethyl sulphoxide (9ml) under an atmosphere of nitrogen wlth the tempereture képt et 20-25. The mlxturo w~s 8~1rred for 10 min, ~nd e ~olution o~ methyl ieothiocyeneté (0.7159) in dimethyl sulphoxide (conteining 7.5% weter) (3ml) wes edded dropwise over 2 min. Stirring wes continued for 0.5h st room tempereture end then methyl iodide (1.52g) wss added dropwise over 2 min. with the temperature kept at 20-25. The solution was stirred at room temperature for 2h., diluted with water (lOOml) and worked up ~ccording to the procedure in Example l(i) to give the title compound (0.96g),Y66.1~. m.p. il3-115.5.

., .

1 7 73~

(iv) According to the procedure in ~xample l(iii), but replsclng PotaQsium tert-butoxide with sodium hydroxide (1.69), nitromethsne (2.449) in dimethyl QulPhoxide (conteining 7.5~ wster) (35ml) snd methyl i~othiocyenate (2.929) in dimethyl ~ulphoxide (conteining 7.5~ water) (5ml) followed by ~lkylstion with methyl iodide (6.259) g~ve the title compound (2.649), Y44.5Z. m.p. 113-116.

Exsmple 2 N-MethYl-l-methvlthio-2-nitroethensmine Pot~ssium hydroxide (20.889) in w~ter (12.4ml) was edded to ~ stirred solution of methyl isothiocy~nate (27.229) snd nitromethane (22.759) in dimethyl ~ulphoxide (185ml), keeping the temPerature et lû-15. Stirring wss continued for 60 min. st 10-15 then the ~olution wa~
; divided into 2 equsl portions (each 120ml).

(i) The fir~t portion wss stirred st 10-15 while dimethyl sulph~te (17.62ml) wss added over 15 min. Stirring wes continued for 30 min. then w~ter (9Oml) WflQ sdded snd the mixture w~s worked up sccording to the Procedure in Ex~mple l(i) to give the title compound l12.459), Y45.1X.
m.p. 112.5 - 114.

, ... ... ... _ . _ . . . . _ _ . ...... .. .... ... . . _ . . . , , ., . . , . . , ,, _, , _ . , ~ .

t 7`.,~

(ii) The second portion was treeted with methyl iodide (11.66ml) ~nd worked up in the same manner to give the title comPound (14.619), Y52.9Z. m.p. 112.S - 114.

Exemple 3 N-Methyl-l-methylthio-2-nitroethenemine Nitromethene (1.059) and methyl i~othiocyenste (1.269) in dry dimethyl sulphoXids (6,71q) ws~ ~dded over 70 min. to e stirred suspenslon of sodium hydride (0,419) in dimethylformemlde (4.3ml) with the tempereture kept below 25. Stirring wes continued for 3h. then methyl iodide (2.459) wss added over 15 min. keeoin9 the tempersture below 30. The resulting solution wes ~tirred for 30 min., weter (9ml) was edded and the solution wes worked up according to the procedure in Example l(i) to give the title comPound. (1.30g~,Y50.8Z. m.p. 113.5-115.5.

Exemple 4 N-Methyl-l-methvlthio-2-nitroethenemine Nitromethane (22.79) was added over 8 mln. to e stirred suspenslon of fleke potassium hydroxide (20.~69) in 1 J ~ ~3 7 32 dimethyl ~ulphoxide (157.5ml) end water (6.4ml) keeping the temperature et 15-20. A solution of methyl isothiocyanate (27.199) in dimethyl sulphoxide (27ml) and weter (lml) was edded droPwise over 20 min. keeping the tempersture et 15-25. Stirring wes continued for e further lh. et room tempereture end methyl iodide (52.78q) wes edded over 10 min. keeping the tempereture et 15-2û.
The resulting mixture wes stirred for e further lh. et room temperature then weter (178ml) wes edded end the mixturs wae worked up according to the procedure in Exemple 1 (i) to give the title compound (25.6893, Y46.6Z.
m.p .113-116.

Example S

N-t2-~5-(DimethYlsmino)methyl-2-furanvlmethylthio]ethyl]
N'-methYl-2-nitro-1,1-ethenediemine A solution of 2-[5-(N,N-dimethyleminomethyl)-2-furen-methylthio]ethylamine (32.19) in weter (25ml) wes edded dropwise over 4h. to e stirred solution of N-mejthyl-l-methylthio-2-nitroethenemine (239) in weter (40ml) at 50.
The reection mixture wes heeted at 50 for e further 2h.
end then heated to 90. Methyl i~obutyl ketone (150ml) wss edded to the solution and the weter removed by ezeotroDIc dl~tllletion The ~olutlon w~ cooled at ~0 .
' , -- 1 3~732 end ch~rcoal (1.59) edded. The mixture wa~ filtered, the chercoel residue weshed with methyl isobutyl ketone ~50ml) snd the combined filtrate snd wsshings were cooled to 0.
The tltle compound (399) m.p.68-70 crystsllised snd wss filtered off.

; ' ' ' ' ' ' ' ' '

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for the preparation of a compound of the general formula (III) (CH3)2NCH2ACH2S(CH2)2NHC(=CHNO2)NHCH3 (III) wherein A represents or which comprises the steps of:

(i)(a) generating the carbanion of nitromethane by reaction of nitromethane with a base, reacting the carbanion of nitromethane with methyl isothiocyanate in the presence of dimethylsulphoxide as solvent to produce a compound of formula (I) (I) wherein Q is a cation derived from the base used to generate the carbanion of nitromethane;

(b) for the production of compounds of the general formula (I) wherein Q is hydrogen, reacting the compound of formula (I) in which Q is a cation with acid to produce the compound of formula (I) in which Q is hydrogen;

(ii) alkylating the compound of formula (I) in which Q
is hydrogen or a cation to produce a compound of formula (II) (II) wherein R1 is a C1-4alkyl group; and (iii) reacting the compound of formula (II) with an amine of formula (IV) (CH3)2NCH2ACH2S(CH2)2NH2 (IV) wherein A is as defined above, to produce the compound of formula (III).

2. A process as claimed in Claim 1, wherein A is .

3. A process as claimed in Claim 1 or Claim 2 wherein R1 is CH3.

4. A process as claimed in Claim 1 wherein the alkylation of the compound of formula (I) is conducted using an alkylating agent selected from the group consisting of alkyl halides and dialkyl sulphates.

5. A process as claimed in Claim 4 wherein the alkylating agent is selected from the group consisting of methyl bromide and methyl iodide.

6. A process as claimed in Claim 4 wherein the alkylating agent is dimethyl sulphate.