Note: Descriptions are shown in the official language in which they were submitted.
3L~97379~
1 This invention relates to an improved process for the
synthesis of amino compounds, i~ particular 2-amino-2-
alkylthio-l-nitroethylenes and to the compounds so
produced. Such a process is particularly use~ul ~or the
producti~n o~ certain compounds which are intermediates
for the production of histamine H2-antagonists. Such
compounds are described in our British Patent specification No.
1421792. A step in the process presently available for the
production o~ many o~ these compounds involves the
displacement of a~ alkylthio e.g., a methylthio group
by an amino group and in certain cases, ~or example where
the amine is not very reactive, this displacement may not
take place easily. It is an object o~ the present i~vention
to increase the e~iciency o~ such displacement reactions.
According to the pre~ent inve~tion we there~ore provide
a proce~s wherein a compound o~ the Formula I:
AS
\ C = CffN02
A-S0
FORMlLA I
2~ wherein A is lower alkyl is reacted ~ith an amine of
Formula II: .
R NH2
FO~MULA II
--
wherein R is aryl such as phenyl, aralkyl such as benzyl
or Rl;
Rl is lower alkyl, alkoxy, tri:eiuoroethyl, (CH2)nR2 or
~etC~2Z(C~2)2; Het is an imidazole, thiazole, pyridine,
isothiazole, oxazole, isoxazole, triazole or thiadiazole
ring, which ring is optionally substitued by lower alkyl,
--2--
~7~74
l hydroxyl, lower alkoxy,~ chlorine or bromine; Z is
sulphur or methylene: n is an integer from 1 to 12; and
R2 is hydroxy, lower alkoxy or lower alkylamino.
The compounds produced by the process of the present
invention wherein R is Rl i.e. compounds of Formula III
in which R is Rl
- AS
\
C = CHNO2
~- 10 ~ NH
.
FORMULA III
are intermediates'for the production of histamine H2'
' antagonists and may be converted to an H2-antagonist
compound o~ Formula I~:
' R NH
C = CHNO2
R NH
.
FOR.UULA IV - --
by reaction thereof by the me-thods such as described i~ our
2~ specification No. 1421792 for example with an amine o~
formula R3NH2 wherein R3 has the same signficance as R
but with the proviso that if Rl is not HetCH2~(C~2)2 then
R3 must be HetC~2Z(CH2)2
30 Throughout the present specification, by the term ''lower
alkyl" we mean an alkyl group containing from 1 to 4 carbon
atoms.
The process of the present invention; when carried out
between equivalent amounts of the compounds o~ formulae I
and Il results in the production of the compound of
Formula III
: -3-
~737~
1 without the formation of any significant amounts o~ the
bis compound of Formula Y:
R NH
\
C = CHN02
NH
.
~O~IULA V
- ~ .
` 10 and this selectiv.ity may in certain cases be desirable.
The process of the invention may, in general, be carried
out under mild conditions.. For example gradual addition
- of a solution o~ the amine of Formula II to a stirred
solution of the compound o~ Formula I at a temperature of
from 15-40C normally ~esults in production of the
required compound o~ Formula III which may then ~e isolated
from the reaction mixture and puri~ied by congentional
methods: -The reaction has been found to proceed success-
fully even when using amines which-are normally comparatively
unreactive e.g.:, those of Formu}a II wherein R is alkoxy
or 2,2,2-trifluoroethyl.
The compoundof Formula I may be produced by treatment of
the corresponding compound of~ Formula VI:-
:
AS
C= C~O
2 .
~,
3~ AS
FO~IULA VI
:,
-4-
~g319737~
wherein .4 has the above significanc~ with an o~idizing
age~t such as hydrogen percæide. This reaction may ~e
carried out in a suitable solvent such as acetic acid.
.
In the process of our invention A is most conveniently
methyl. The process is particularly use~ul ~or the
productio~ o~ compounds o~ Formula IIIa wherein Rl is
alko~y, (Ca2)~ R2 or Het CE2Z(CH2)2.
Thus, in accordance with the present teachings,
a process is provided for the production of a compound of the
formula
\C = C~ N02
A-S ~
wherein A is a lower alkyl;
~herein a compound of th~ f~r~ a
AS
\ C = C~l N02
AS
is reacted with an Qxidising agent.
--5--
7~3~74
By a further aspect provided, in accordan~e
with the present teachings, a compound of the formula
RN~
>C = C~I N02
wherein A is lower alkyl; and R is phenyl, benzyl, lower alkyl,
trifluoroethyl, or Het CH2Z(CH2)2; Het is an imidazole, thiazole
or pyridine ring, which ring is optionally substituted by lower
alkyl or lower alkoxy; Z is sulphur or methylene.
Those c~mpou~d ~herei~ R~ etC~ Z(C~2)~ are particularly
pre~erred when Het i~ a~ imidazole,thiazole or pyridine ring
optio~ally substituted by methyl, hydro~y or chiorine.
: Speci~ic-compounds which may be co~eniently prepared by
~he proce~ o~ the prs~ent inventio~ include:
a) l-nitro-2-methylthio-2-methylaminoethylene
: b). l-nitro-2-~ethylthio-2-ethylaminoethylene
~2Q c) .l-~itro-2-methylthio-2-(2,2,2-tri~luoroethylamino)-
ethylene
d) l-~itro-2-~ethylthio-2-methoxyaminoethylene
~ e) l~ ro-2-methylthio-2-~2-(~5-methyl~4-imidazolyl)-
: ~ methylthio)ethylam~no]ethyle~e
nitro-2-~ethylthio-2-[2-((2-thiazolyl~methylthio)-
ethylamino]ethylene~
. g) l-nltro-2-methylt;hio-2-~4-(2-thiazolyl)butylamino]-
: ethylene
:~ : h) l-nitro-2-methy~thio-2-phenylami~oethylene
i) 1- itro-2 methylthio-2-benzylaminoethylene
Compou~d~ (a) to:(g3 above, which are all intermediates
~or ~ -a~tagoni.sts, may be reacted ~ith a suitable amine
according to the process of the prssent inventio~ to yield
a~ H2-antagonist compounds such as:
: ~ :
a) l-nitro-2-methylamino-2-~2-((5-methyl-4-imida~olyl)-
methylthio)ethylami~o]ethylene
b) l-nitro-2-ethylamino-2-[2-((5-methyl-4-imidazolyl)-
- methylthio)ethylamino~ethylene
-5a-
~)9737~
1 c) 1-nitro-2-(2,2,2-trifluoroethylamino)-2-[2-((5-
methyl-4-imidazolyl)methylthio)ethylamino]ethylene
d) l-nitro-2-methoxyamino-2~[2-((5-methyl-4-imidazolyl)-
methylthio)ethylamino]ethylene
e) l-nitro-2,2-bis-[2-((5-methyl-4-imidazolyl)methylthio)-
ethylamino3ethylene
nitro-2-methylamino-2-[2-((2-thiazolyl)methylthio)-
ethylamino]ethylene
g) l-nitro-2-methylamino-2-[4-(2-thiazolyl)butylaminol-
ethylene.
It ~ill be understood that the compounds oi Formula I and III
to VI, may e~ist as two~distinct geometrical isomers i.e.,
in the "Z" and "E" Porms. Unless speciPically stated to
15 the contrary any reference to such a compound is intended to
refer to the "Z" and "E" forms individually as well as to
mixtures o~ the two Porms.
The invention is illustrated but in no way limited by the
~ollowing-Examples 2-9. Example 1 shows the preparation of
a starting material.
E~A~PLE 1
; To a stirred solution in acetic acid (4,500 ml) of l,l-bis-
methylthio-2-nitroethylen~ (165 g) at 60 was added over
15 minutes 30% (100 volume) hydrogen peroxide (113 ml) and
the reaction mixture maintainea' with stirring, at 60 ~or
17 hours. Evaporatio~ oi the solvent u~nder reduced pressure
gave a resid~e which was taken up in methylethylketonc, r~-
evaporated and ~inally crystallised Prom methylethylketone
to yield the title product as a yellow solid m.p. 137-143.
~Further purification yielded the pure "Z" and "E" isomers.
One o~ these had m.p. 145-1~8 and ~'rom the mother liquors the
other isomer was obtained a~ter ~urther working up and re-
crystallisation ~rom methylal, m.p. 90-93.
--6--
~9~7~7~
1 Found: C, 26.7; H, 3.9; N, 7.7; S, 35.1ao C4H7N03S2
requires: C, 26.5; H, 3.g: N, 7.7; S, 35.4$
E~YAI~PLE 2
l-Methylthio-l-methylamino-2-nitroethylene
.
A solution in methanol (100 ml) of methylamine (9.4 g)
was added dropwisq over 10 minutes to a stirred solution
in methanol (500 ml) at 25-30 of l-methylsulphinyl-l-
methylthio-2-nitroethylene (18.1 g). T.L.C. analysis
- indicated immediate complete disappearance of the sulphoxide.
- Evaporation of the reaction mixture yielded an oily solid
which, on recrystallisation from isopropanol gave the tit}e
product (8.1 ~) m.p. 113-113.5.
Found: C, 32.4; H1 5.4; N, 18.9; S, 21.6% C4H8N202S
requires: C, 32.4; H, 5.5; N, 18.8; S, 21.8
EXAMPLE 3
1- Methylthio-l-ethylamino-2-nitroethyl~ene
A solution in methanol (5 ml) of ethylamine (225 mg) was
added dropwise ov~r 2 minutes to a stirred solution in
methanol (30 ml) at 32 o~ l-methylsulphinyl-l-methylthio-
2-nitroethylene (906 mg). Evaporation of the reaction
mixture gaYe a~ oil which was cryst~llised from isopropanol
to give the title product (230 mg) m.p. 66-67.5.
Found: C, 36.8; H, 6.2; ~, 17.0~ C5~10N20~S -
re~uires: C, 37.0; H, 6,2; N, 17.3%EYAMPLE 4
3~
l-Methylthio-l-phenylamino-2-nitroethylene
. ~ . . . .......... . . .
A solution o~ aniline ~466 mg) in methanol (5.0 ml) was
added dropwise over 3 minutes to a stirred solution in
methanol (30 ml) at 35 o~ l-methylsulphinyl-l-methylthio-
2-nitroethylene (906 mg). The reaction mixture was cooled
to 0 and the crude product precipitated (755 mg). ~.e-
crystallisation from metha~ol-acetone gave the title
compound~ m.p. 145-149.
-7
~737~
l (Found: C, 51.a; H, 4.8; N, 13.2; S, 15.2~o CgHloN202S
requiFes: C, 51.4; H, 4.8; N, 13.3; S, 15.2~o
- ' EXAMPLE_5
1-Methylthio-l-~enzylamino-2-nitroethylene
A solution oi benzylamine (536 mg) in methanol (5.0 ml)
was added dropwise over 2 minutes to a stirred solution
in methanol (30 ml) at 38 of l-methylsulphinyl-l-methyl-
thio-2-nitroethylene (906 mg). The reaction mixture was
cooled to -5 and the precipitated product separated t595
mg). Recrystallisation from isopropanol gave the~title
product, as white needles, m.p. 110.
Found: C, 53.4; H, 5.4; N, 12.4; S, 14.3% CloH12N202S
1~
requires: C, 53.5; H, 5.4; N, 12.5; 14.3%
EXAh~LE 6
l-Methylthio~ 4-(2-thiazolyl)butylaminol-2-nitroethylene
A solution of 2-t4-amlnobutyl)thiazole (1.56 g) in methanol
(35 ml) was added dropwise over 30 minutes to a stirred
solution of l-methylsulphinyl-l-methylthio-2-nitroethylene
.81 g) in methanol (60 ml). The product was isolated as
in the previous Exæmples and recrystallised ~rom isopropanol
-to give the title product, m.p. 75.5 ~76.
Found: C, 43.8; H, 5.5; N, 15.1; S, 23.~% C10~15N302S2
requires: C, 43.9: ~, 5.5: N, 15.4: S, 23.4%
EXA~PLE 7
__
l-~ethylthio-l-t2,2,2-tri~luoroethylamino)-2-nitroethylene
A solution o~ 2,2,2~tri~1uoroethylamine (4.0 g) in methanol
(45 ml) was added dropwise to a suspension of l~methyl-
sulphinyl-l-methylthio-2-nitroethylene (3.6 g~ in methanol
-8-
" 10~7;~74
(150 ml) at 20 for 24 hours. Evaporation of the
reaction mi~ture and recrystallisation from ether
gave the title compound as a pale orange crystalline
solid m.p. 101-102.
(l~ound: C, 28.0 H, 3.2 N, 12.9- S, 15.1%. C5H7F3N202S
requires: C, 27.8 H, 3.3: N, 13.0- S, 14.870.
EXA~LE 8
l-Nitro-2-methylthio-2-~2-((5-methyl-4-imidazolyl)meth~rlthio)-
10 ethylamino]ethylene
A solution of 2-[(5-methyl-4-imidazolyl)methylthio]ethylamine
(8.56 g) in methanol (115 ml) was added dropwise over 13
minutes to a stirred solution of l-methylsulphinyl-l-methyl-
thio-2-nitroethylene (9.06 g) in methanol (150 ml) at 40.
15 Evaporation of the reaction mixture and recrystallisation of
the resultant solid from isopropanol yielded the title product
(7.15 g), m.p. 147-150.
(Found: C, 41.7; H, 5.6; N, 19.1; S, 21.7% CloH16N402S2
requires: C, 41.6, H, 5.6; N, 19.4; S, 22.2%.
EXAh~PLE 9
l-Nitro-2-methylthio-2-[(2-thiazolylmethylthio)ethylamins]-
ethylene
. _ _
An aqueous solution (25 ml) of 2-(2-thiazolylmethylthio)-
ethylamine (1.74 g) was added dropwise over 10 minutes to a
stirred solution in methanol (60 ml) at 35 of l-methyl-
sulphinyl-1-methylthio-2-nitroethylene (1.81 g). Cooling
to -5 yielded a solid product which on recrystallisation
from isopropanol gave the title product (1.63 g) m.p. 90-
92
Found: C, 37.3; H, 4.5; N, 14.5; S, 32.7% C9~113N302S3
requires: C, 37.1; H, 4.5; N, 14.4; S, 33.0%.
-
374
1 EXAMPLE lO
l-Nitro-2-methylthio-2-~2-((3-metho~y-2-pyridyl)-
methylthio)ethylamino]ethylene
A solution of 2-[2-aminoethylthiomethyl]-3-methoxypyridine
S t2.1 g) in methanol (33 ml) was added over 25 minutes to
a stirred solution o~ l-methylthio-l-methylsulphinyl-2-
nitroethylene (2.1 g) in methanol (75 ml) at 30. After
sta~di~g ~or an hour the solution was concentrated to
give a yellow-brown oil which was crystallised from
ethanol/ether to yield l-nitro-2-methylthio-2-[2-((3-
methoxy-2-pyridyl)methylthio)ethylamino]ethylene (1.9 g),
m.p. 87.5 - 88.5.
(Eound: C, 45.5; Hj 5.4; ~, 13.3% C12Hl~N3O3S2
requires: C, 45.7; H, 5.4; N, 13.3%
EXAMPLE 11
. Reaction in the procedure o~ E~ample 2 o~ i-methylsulphinyi-
l-methylthio-2-nitroethylene with the ~ollowing amines:
;~ : methoxyamine
4-aminobutanol
2-methoxyethylamina and
2-methylaminoethylamine
yielded the ~ollowing products respectively:
l-nitro-2-methoxyamino-~-methylthioethylene,
1-nitro-2-(4-hydroxybutyl)amino-2-methylthioethylene,
l-nitro-2-(2-metho~yethyl)amino-2~methylthioethylene and
l-nitro-2-(2-methylaminoethyl)~mino-2-methylthi3ethylene.
EXA~LE 12
3S
Reaction in the procedure o~ Example 2 of l-methylsulphinyl-
--10--
374
1 1-methylthio-2-nitroethylene with the following compounds:
a) 3-chloro-Z-[(2-aminoethyl)thiomethyl]pyridine,
b) 3-bromo-2-[(2-aminoethyl)thiomethyl]pyridine,
c) 3-hydroxy-2-~(2-aminoethyl)thiomethyl]pyridine,
d) 3-~(2-aminoethyl)thiomethyl]isothiazole,
e) 4-methyl-5-[(2-amlnoethyl)thiomethyl]oxazole,
~) 3-~(2-aminoethyl)thiomethyl~isoxazole,
g) 3-[(2-aminoethyl)thiomethyl]-1,2,4-triazole and
h) 2-[(2-aminoethyl)thiomethyl]-1,3,4-thiadiazole yielded
the following products respectively:
1~
a) l-nitro-2-~2-((3-chloro-2-pyridyl)methylthio)ethylamino]-
2-methylthioethylene,
b) l-nitro-2-[2-((3-bromo-2-pyridyl)methylthio)ethylamino]-
2-methylthioethylene,
c) 1-nitro-2-~2-((3-hydxoxy-2-pyridyl)methylthio)ethylamino}-
2-methylthioethylene,
d) l-nitro-2-[2-(3~isothiazolylmethylthio)ethylamino]-2-
methylthioethylene,
e) l-nitro-2-~2-((4-methyl-5-oxazolyl3methylthio)ethylamino]-
2-methylthioethylene,
nitro-2-[2- (3-isoxazolylmethylthio) Qthylamino]-2-
methylthioethylene,
g) l-nitro-2-E2-((3-(1,2,4-triazolyl)methylthio)ethylamino~--
2-methylthioethylene and
h) l-nitro-2-~2-((2-(1,3,4-thiadiazolyl)methylthio)ethylamino~-
2-methylthioethylene.
.
--11--
