CA1097374A - 1-alkylsulphinyl-1-alkylthio-2-nitroethylenes - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

A process is disclosed for the preparation of amino compounds and particularly compounds of the formula

Description

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 FORMlLA I

2~ wherein A is lower alkyl is reacted ~ith an amine of Formula II: .

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, ~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.

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.

~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 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.

~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 " 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-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%.

-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%

. 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 Reaction in the procedure o~ Example 2 of l-methylsulphinyl-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.

.

Claims (7)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for preparing a compound of the formula wherein A is a lower alkyl, which comprises reacting a compound of the formula wherein A is defined above, with an oxidizing agent and there-after where required as separating the product into geometric isomers.

2. A process according to claim 1 in which the oxidizing agent is hydrogen peroxide.

3. A process according to claim 1 or claim 2 in which the reaction is carried out in acetic acid.

4. A process according to claim 2 in which one equivalent of hydrogen peroxide is used.

5. A process according to claim 4 which is carried out at 60°.

6. A process for preparing 1-methylsulphinyl-1-methylthio-2-nitroethylene which comprises reacting 1,1-bis-methylthio-2-nitroethylene with hydrogen peroxide.
7. A process according to claim 6 where the product is separated by crystallisation into geometrically pure isomers.

8. A compound of structure and geometirc isomers thereof in which A is lower alkyl whenever prepared or produced by the process of claim 1 or by their obvious chemical equivalents.
9. 1-methylsulphinyl-1-methylthio-2-nitroethylene whenever prepared or produced by the process of claim 6 or by their obvious chemical equivalents.

10. A compound of claim 9 in the form of a substantial-ly pure geometric isomer whenever prepared by a process of

claim 7.