PREPARATION OF AMINE DERIVATIVES

PREPARATION DE DERIVES DE L'AMINE

English Abstract

A B S T R A C T
PREPARATION of Amine Derivatives
Compounds of formula (II)
<IMG> (II)
in which R1 is C1-4 alkyl, preferably methyl, are prepared
by reaction of a compound of formula (I)
<IMG> (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.

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 an
N-methyl-1-alkyl-thio-2-nitroethenamine derivative of
the general formula (II).
<IMG> (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)
<IMG> (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).
13

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.
14

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.

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~
-3-
The present invention pro~ides a process for the
preparation of a compound of formula (I)
QS
~C=CHN02 (I)
CH3NH
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)
CH3

~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~
-- 8 --
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~
-- 10 --
(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~
--11--
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.