FIELD OF INVENTION
This invention relates to a novel product, 2-arylthio-2-methylamino-l-nitroethene5 and more particularly to a processes for the preparation of the title compound.
DESCRIPTION OF THE RELATED ART
Ranitidine and nizatidine, effective as a histamine H2 receptor antagonist, and useful anti-ulceratives, have been synthesized in a very well known process using intermediate 2-alkylthio-2-methyl amino-1-nitroethene. However, one of the major drawbacks of the process is the release of methyl mercaptan as one of the byproducts. One of the existing effluent management methods involves combustion of methyl mercaptan to sulfur dioxide which, in many instances, ends with incomplete conversion thus increasing burden on the environment. Another method drawing attention, wherein the methyl mercaptan gas is scrubbed with alkaline solution or absorbed over charcoal, is not cost-effective.
Reference is made to U.S. Pat. No. 5,605,635 (Feb. 25, 1997) wherein a process for purifying gaseous or liquid effluents containing sulfur-containing derivatives by basification of the effluent to be treated at pH>9 was described.
Reference is also made to U.S. Pat. No. 4,729,835 (Mar. 8, 1988) wherein a process for waste treatment of dimethyl disulphide was disclosed using hydrogen peroxide at a pH 8.5 to 1L5 in the presence of tungstate catalyst. The drawbacks in the above processes are that there is no mention of recovering of any value-added product except to control the emission of the foul smelled gases.

Reference is further made to U.S. Pat. No. 4,239,696 (Dec. 16, 1980) wherein alkylsulfonic acids are prepared by oxidation of alkyl mercaptan or dialkyl disulfide with hydrogen peroxide. This is a synthetic method of preparation of alkylsulfonic acids and this work was not directed for the elimination of the obnoxious gases of effluent streams generated at chemical industries.
Reference is made to U.S. Pat. No. 6,927,305(Aug.9, 2005) wherein B.M.Choudary et.al have reported in situ oxidation of the methyl mercaptan at 40oC to methylsulfonic acid US. However, uncontrolled and misinform evolution of the gas at the reaction temperation of 40 OC leaded to incomplete converion hence the unreacted gases was nedded to be scrubbed. In addition, rectifying the highly corrosive methanesulfonic acid from 20% to 99% is very difficult and industrially not viable for drug manufacturers. Notwithstanding their time-honored positions, those manufacturing methods can be hardly said satisfactory from the contemporary industrial standpoint, for they disclose certain problematic aspects. Hence there has been a research interest on a process that would not only minimize the byproduct methyl mercaptan but also produce a byproduct of industrial importance.
Hence it drew attention of the present inventors to look into an intermediate, for the preparation of ranitidine and nizatidine, that would render a byproduct of industrial importance e.g. thiophenols more preferably 2-nitrothiophenol, the amine analogue of which is a very valuable raw material for the manufacture of diltiazem. This being the goal, the present invention describes a novel intermediates 2-arylthio-2-methyl amino-1-nitroethene, for an environmentally safe manufacture of ranitidine and nizatidine, and a process for the preparation thereof

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a a novel compound, 2-arylthio-2-methyl amino-1-nitroethene, of formula I.
In one embodiment of the invention, there is provided a process for producing a novel compound, 2-arylthio-2-methyl amino-1-nitroethene, of formula I

where R is H, 2-CH3, 3.CH3,4-CH3, 2-OCH3, 3-OCH3, 4-OCH3, 2-CF3, 3-CF3, 4-CF3, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-NO2, 3.NO2, 4-NO2, 2-NHCOCH3, 3-NHCOCH3, and 4-NHCOCH3
by reacting the diazonium salt of formula II

where X= F, CI, Br or BF4 with the product of formula III.

In yet another embodiment of the invention, there is provided a manufacturing process for producing 2-arylthio-2-methyl amino-1-nitroethene of formula I which comprises reacting diazonium salt formed by diazotizing aniline derivative with nitroethenamine derivative of formula III, in a aqueous organic medium at a temperature of 40 to 70 °C.

In still another embodiment of the invention, the aqueous medium contains 50 - 75% of the organic solvent selected from the group dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, dimethyl sulfoxide and solfolane either singly or in combination of two or more of the solvent.
In yet another embodiment of the invention, the product of formula I is isolated by extracting with an organic solvent like toluene xylene, ethyl acetate, chloroform or ketonic solvent.
DETAILED DESCRIPTION OF THE INVENTION
The time-honored diazotization reaction is carried out typically by reacting the arylamine with a mineral acid and sodium nitrite in aqueous solution. Although choice of the mode of reaction is optional, it is the typical practice to add sodium nitrite or an aqueous solution of sodium nitrite to aqueous solution of a mineral acid into which arylamine has been dissolved beforehand.
There can be cited hydrochloric acid and sulfuric acid as a few examples of the mineral acid to be employed for the diazotization reaction. The amount of mineral acid to be employed per mole of arylamine is to be preferably in the range of 1.0 to 10.0 moles, and more preferably 2 moles. In cases where the amount of mineral acid is too short, the yield of diazonium salt drops off, and where it is on the contrary excessively large, the efficiency declines, eventhough the reaction per se is not adversely affected. Since neither case is desirable, an aqueous solution of sodium acetate was added to reduce the free hydrochloric acid.

As for the type of water to be selected for use in the reaction as disclosed in the present invention, industrial water, ion-exchanged water, pure water, and distilled water are all suitably useable. The amount of water, to be employed in the diazotization reaction, is to be preferably 1.5 to 10.0 times, and particularly preferably 2.0 to 5.0 times as much as arylamine by weight. In cases where the amount of water is too short, the concentration of the crystal of the mineral acid salt formed from arylamine in the reactant liquid gets too high to employ agitation. In cases where the amount of water is excessively large, the yield drops off, eventhough the reaction is not disrupted at all. Hence, neither case is desirable.
For diazotization of arylamine, sodium nitrite is employed as the diazotizing agent. Sodium nitrite, which is available normally in the solid state, may be added to the reaction system as it is, while the typical practice is to employ it in the state of being dissolved in water. The amount of sodium nitrite per mole of the raw material arylamine is to be preferably in the range of 0.8 to 1.5 moles, and more preferably in the range of 0.9 to 1.0 moles. In cases where the amount of sodium nitrite is too short, the conversion rate of the raw material declines to an undesirable degree. On the contrary, impurities in the reaction product increase with use of an excessive amount of sodium nitrite. Therefore, neither case is desirable. As for the fashion of adding sodium nitrite, there is imposed no particular limitation. That is to say, it may be added by dropping or pouring into the reactant liquid.
The temperature at which addition and reaction of sodium nitrite are to be made may be set within the range of -20 to 0 OC, and preferably -20 to -10 °C. With reaction temperatures kept to below the lower ends of said ranges, the reaction rate gets slower.

On the contrary, when the reaction temperature exceeds the upper end of said ranges, decomposition of diazonium salt progresses with the result that the yield drops off and more impurities come to be included. Therefore, deviation from said ranges is by no means desirable.
There is no particular limitation to the time frame in which addition of sodium nitrite is to be completed, but the time frame may be regulated in the light of the state of bubbling of generated nitrogen gas and cooling capacity. It is typically 0.1 to 24 hr. The reaction may be terminated as soon as the addition of sodium nitrite is finished, although the reaction is to be terminated typically after having stirred the reactants for 0.1 to 3 hr. A solution of 2-methyl amino-1-nitroethenethiolate is prepared by slow addition of a solution of methyl isothiocyanate in dimethyl sulfoxide to a solution of nitromethane in dimethyl sulfoxide kept at 5 °C. it is followed by slow addition of an aqueous KOH solution over a period of 40 min and solid potassium hydroxide maintaining a temperature of ca. 10 °C. The mixture is then stirred for 3h.
The aforesaid reaction is suitably carried out by adding 2-methyl amino-1-nitroethenethiolate solution with the aqueous solution of diazonium salt formed from arylamine. The preferred method for carrying out the aforesaid reaction is to drop the aqueous solution of diazonium salt formed from arylamine into solution of 2-methyl amino-1-nitroethenethiolate. As the aqueous solution of such a diazonium salt, there may be employed the reaction mixture obtained by the diazotization reaction as it is. The amount of 2-methyl amino-1-nitroethenethiolate to be employed in said reaction is to be preferably 0.9 to 1.2 moles, and more preferably 1 moles on the basis of sulfur atom per mole of diazonium salt formed from arylamine. The grounds for selecting said ratios

are that in cases where the amount of 2-methyl amino-1-nitroethenethiolate is too little, the achievable yield of title product is only so low and that if the amount is excessive, the resultant effects are a low purity, increased impurities and a decline in the production efficiency for 2-arylthio-2-methyl amino-1-nitroethene.
It is desirable that the temperature at which the aqueous solution of diazonium salt formed from arylamine is added and reacted is fixed within the range of 40 to 70 °C, and preferably 60 to 70 °C. At temperatures lower than the aforesaid temperatures the rate of reaction gets too low, and, on the other hand, at higher temperatures the yield drops off. There is no particular limitation to the time frame in which addition of the aqueous solution of diazonium salt formed from arylamine is to be completed. The time frame may be regulated in accordance with cooling capacity. It is typically 1 to 24 h, preferably 2h. From the point in time where the aqueous solution finishes to be added, however, it is preferable to terminate the reaction by heating upon a steam-bath for one hour to allow any remaining diazothioether to decompose completely.
Purification of the product is carried in a method as follows. The reaction mixture is acidified with hydrochloric acid and after adding zinc, is refluxed for one hour in order to reduce any disulfide to thiol. The content of the flask is cooled and extracted with ether. A brown, solid tar, which was insoluble in acid, alkaili or ether, remained behind. The brown ether extract was repeatedly washed with 5% sodium hydroxide solution until the alkaline solution no longer turned brown, then with dilute hydrochloric acid, water and finally dried over sodium sulfate. After removal of ether, the remaining oil was distilled to afford the 2-(2-nitrophenyl)thio-2-methylamino-1-nitroethene with high purity.

EXAMPLE 1
To a 250mL three-necked flask containing 13.8 g of 2-nitroaniline are added 12mL of concentrated hydrochloric acid and 25 mL of hot water. The contents of the flask are heated to about 85° to dissolve 2-nitroaniline; then 8 mL. of concentrated hydrochloric acid is added. The mixture is cooled in an ice-salt bath and stirred rapidly in order to precipitate the hydrochloride as fine crystals. Cracked ice (lOg.) is added, and a solution of 7g. of sodium nitrite in 20mL water is added dropwise with rapid mechanical stirring during a 2-hour period, while the temperature of the reaction mixture is held between -10° and -5° by cooling with the ice-salt bath. The stirring is continued for 15-20 minutes after the sodium nitrite solution has been added; then a solution of 13.6 g. of sodium acetate trihydrate in 80 ml. of water is added to reduce the free hydrochloric acid and the stirring is discontinued. The diazonium salt solution must be kept cold while the next step is proceeding.
To another 250 mL three-necked flask containing a solution of 6.1g of nitromethane in 20mL dimethyl sulfoxide kept at 5 °C is added slowly a solution of methyl isothiocyanate in 15 mL of dimethyl sulfoxide and the mixture was stirred for 15 min. An aqueous KOH solution ( 3.7g in 2.1 mL water) was added slowly over a period of 40 min followed by 2.7g of solid potassium hydroxide maintaining a temperature of ca. 10 OC. The temperature of the reaction mixture was raised to 20-30 °C and the whole was stirred for 3h.
The solution of diazotized 2-nitroaniline was slowly dropped with constant stirring into the 2-methyl amino-1-nitroethenethiolate solution was held at 60 °C. A yellow precipitate was formed which rapidly decomposed with the evolution of nitrogen

and formation of a brown oil. After the major portion of the diazonium salt solution had been added, the reaction mixture became quite viscous because of the emulsification of the oil. It was finally heated upon a steam-bath for one hour to allow any remaining diazothioether to decompose completely. The final reaction product had a slightly aromatic ethereal odor.
The mixture was then acidified with hydrochloric acid and after adding zinc was refluxed for one hour in order to reduce any disulfide to thiol. The content of the flask was cooled and extracted with ether. A brown, solid tar, which was insoluble in acid, alkali or ether, remained behind. The brown ether extract was repeatedly washed with 5% sodium hydroxide solution until the alkaline solution no longer turned brown, then with dilute hydrochloric acid, water and finally dried over sodium sulfate. After removal of ether, the remaining oil was distilled to afford the 2-(2-nitrophenyl)thio-2-methylamino-l-nitroethene (17.85g, 75 %). m. p. 149-153 °C, purity=99.2 % (HPLC); M/z (M+) 255; Elemental Analyses C, 42.31; H, 3.51 ; N, 16.46 ; S,12.54 ;IR(KBr): 3320, 3168, 2923, 1627, 1597, 1569, 1507, 1429, 1429, 1345, 1283, 1243, 1169, 1100, 1013, 873, 778, 741, 694, 662, 555, 522 cm-1 1H NMR (300 MHz, CDCI3): d (ppm) 8,07 (d, 1H), 7.31 (d, 1H), 6.78 (m, 2H), 6.02 (s, 1H) 3.5 (b, 1H), 2.47 (d, 3H)
EXAMPLE 2
The process of Example 1 was repeated, using 3-nitroaniline instead of 2-nitroaniline to give 2-(3-nitrophenyl)thio-2-methylamino-l-nitroethene (15.2g), purity=99.2% (HPLC); M/z (M^) 255; Elemental Analyses C, 42.33; H, 3.56 ; N, 16.45 ; S,12.52.

EXAMPLE 3
The process of Example 1 was repeated, using 4-nitroaniline instead of 2-nitroaniline to give 2-(4-nitrophenyl)thio-2-methylamino-l-nitroethene (16.3g), purity=99.1% (HPLC); M/z (M+) 255; Elemental Analyses C, 42.30; H, 3.54 ; N, 16.42 ; S,12.55.
EXAMPLE 4
The process of Example 1 was repeated, using 2-methylaniline instead of 2-nitroaniline to give 2-(2-methyl phenyl)thio-2-methylamino-l-nitroethene (11.3g), purity=99.5% (HPLC); M/z (M+) 224; Elemental Analyses C, 53.55; H, 5.39 ; N, 12.42 ; S, 14.25.
EXAMPLE 5
The process of Example 1 was repeated, using 3-methylaniline instead of 2-nitroaniline to give 2-(3-methylphenyl)thio-2-methylamino-l-nitroethene (10.3g), purity=99.6% (HPLC); M/z (M+) 224; Elemental Analyses C, 53.50; H, 5.31 ; N, 12.43 ; S, 14.30.
EXAMPLE 6
The process of Example 1 was repeated, using 4-methylaniline instead of 2-nitroaniline to give 2-(4-methylphenyl)thio-2-methylamino-l-nitroethene (11.8g), purity=99.0% (HPLC); M/z (M+) 224; Elemental Analyses C, 53.52; H, 5.33 ; N, 12.40 ; S, 14.28.
EXAMPLE7

The process of Example 1 was repeated, using 2-methoxyaniline instead of 2-nitroaniline to give 2-(2-methoxyphenyl)thio-2-methylamino-l-nitroethene (10.7g), purity=99.1% (HPLC); M/z (M+) 240; Elemental Analyses C, 50.00; H, 5.04 ; N, 11.61 ; S, 13.29.
EXAMPLE 8
The process of Example 1 was repeated, using 3-methoxyaniline instead of 2-nitroaniline to give 2-(3-methoxyphenyl)thio-2-methylamino-l-nitroethene (lO.lg), purity=99.8% (HPLC); M/z (M+) 240; Elemental Analyses C, 49.95; H, 5.01 ; N, 11.65 ; S, 13.32.
EXAMPLE 9
The process of Example 1 was repeated, using 4-methoxyaniline instead of 4-methoxyaniline to give 2-(4-methoxyphenyl)thio-2-methylamino-l-nitroethene (11.5g), purity=99.4% (HPLC); M/z (M+) 240; Elemental Analyses C, 49.98; H, 5.01; N, 11.62; S, 13.31.
EXAMPLE 10
The process of Example 1 was repeated, using 2-trifluoromethylaniline instead of 2-nitroaniline to give 2-(2-trifluoromethylphenyl)thio-2-methylamino-l-nitroethene (12.4g), purity=99.8% (HPLC); M/z (M+) 278; Elemental Analyses C, 43.12; H, 3.21; N, 10.05; S, 11.51.
EXAMPLE 11

The process of Example 1 was repeated, using 3-trifluoromethylaniline instead of 2-nitroaniline to give 2-(3-trifluoromethyIphenyl)thio-2-methylamino-l-nitroethene (10.8g), purity=99.2% (HPLC); M/z (M+) 278; Elemental Analyses C, 43.14; H, 3.25; N, 10.06; S, 11.54.
EXAMPLE 12
The process of Example 1 was repeated, using 4-trifluoromethylaniline instead of 2-nitroaniline to give 2-(4-trifluoromethylphenyl)thio-2-methylamino-l-nitroethene (10.5g), purity=99.6% (HPLC); M/z (M+) 278; Elemental Analyses C, 43.10; H, 3.201; N, 10.06; S, 11.53.
EXAMPLE 13
The process of Example 1 was repeated, using 2-fluoroaniline instead of 2-nitroaniline to give 2-(2-fluorophenyl)thio-2-methylamino-l-nitroethene (8.3g), purity=99.5% (HPLC); M/z (M+) 228; Elemental Analyses C, 47.36; H, 3.97; N, 12.25; S, 14.02.
EXAMPLE 14
The process of Example 1 was repeated, using 3-fluoroaniline instead of 2-nitroaniline to give 2-(3-fluorophenyl)thio-2-methylamino-l-nitroethene (7.2g), purity=99.1% (HPLC); M/z (M+) 228; Elemental Analyses C, 47.32; H, 3.95; N, 12.21; S, 14.04.
EXAMPLE 15

The process of Example 1 was repeated, using 4-fluoroaniline instead of 2-nitroaniline to give 2-(4-fluorophenyl)thio-2-methylamino-l-nitroethene (6.8g), purity=99.5% (HPLC); M/z (M+) 228; Elemental Analyses C, 47.34; H, 3.93; N, 12.26; S, 14.04.
EXAMPLE 16
The process of Example 1 was repeated, using 2-chloroaniline instead of 2-nitroaniline to give 2-(2-chlorophenyl)thio-2-methylamino-l-nitroethene (6.3g), purity=99.0% (HPLC); M/z (M+) 244; Elemental Analyses C, 44.15; H, 3.65; N, 11.42; S, 13.01.
EXAMPLE 17
The process of Example 1 was repeated, using 3-chloroaniline instead of 2-nitroaniline to give 2-(3-chlorophenyl)thio-2-methylamino-l-nitroethene (7.1g), purity==99.6% (HPLC) ); M/z (M"") 244; Elemental Analyses C, 44.13; H, 3.64; N, 11.41;S, 13.04.
EXAMPLE 18
The process of Example 1 was repeated, using 4-chloroaniline instead of 2-nitroaniline to give 2-(4-chlorophenyl)thio-2-methylamino-l-nitroethene (6.8g), purity=99.5% (HPLC) ); M/z (M+) 244; Elemental Analyses C, 44.16; H, 3.61; N, 11.45; S, 13,03.
EXAMPLE 19
The process of Example 1 was repeated, using 2-bromoaniline instead of 2-nitroaniline to give 2-(2-bromophenyl)thio-2-methylamino-l-nitroethene (7.2g), purity=99.3% (HPLC) ); M/z (M+) 289; Elemental Analyses C, 37.38; H, 3.10; N, 9.62; S, 11.01.

EXAMPLE 20
The process of Example 1 was repeated, using 3-bromoaniline instead of 2-nitroaniline to give 2-(3-bromophenyl)thio-2-methylamino-l-nitroetliene (7.8g), purity=99.7% (HPLC); M/z (M+) 289; Elemental Analyses C, 37.35; H, 3.12; N, 9.66; S, 11.07.
EXAMPLE 21
The process of Example 1 was repeated, using 4-bromoaniline instead of 2-nitroaniline to give 2-(4-bromophenyl)thio-2-methylamino-l-nitroethene (6.9g), purity=99.4% (HPLC); M/z (M+) 289; Elemental Analyses C, 37.36; H, 3.11; N, 9.64; S, 11.06.
EXAMPLE 22
The process of Example 1 was repeated, using N-(2-aminophenyl)acetamide 2-bromoaniline instead of 2-nitroaniline to give N-(2-(l-(methylamino)-2-nitrovinylthio)phenyl)acetamide (8.2g), purity=99.2% (HPLC); M/z (M+) 267; Elemental Analyses C, 49.41; H, 4.91; N, 15.70; S, 12.02.
EXAMPLE 23
The process of Example 1 was repeated, using N-(3-aminophenyl)acetamide instead of 2-nitroaniline to give N-(3-(l-(methylamino)-2-nitrovinylthio)phenyl)acetamide (9.6g), purity=99.5% (HPLC)); M/z (M"^ 267; Elemental Analyses C, 49.45; H, 4.90; N, 15.74; S, 12.01.

EXAMPLE 24
The process of Example 1 was repeated, using N-(4-aminophenyl)acetamide instead of 2-nitroaniline to give N-(4-(l-(methylamino)-2-nitrovinylthio)phenyl)acetamide (10.lg), ( purity=99.0% (HPLC)); M/z (M+) 267; Elemental Analyses C, 49.43; H, 4.94; N, 15.72; S, 12.00.

We claim
1. A novel compound of formula I, which in turn may be a very valuable intermediate
for the manufacture of anti-ulceratives e.g. Ranitidine and Nizatidine.

where R is H, 2-CH3,3- CH3, 4- CH3, 2-OCH3, 3- OCH3,4- OCH3, 2-CF3, 3- CF3, 4-CF3, 2-F, 3- F, 4- F, 2-Cl, 3- CI, 4- CI, 2-Br 3- Br, 4- Br, 2-NO2,3- NO2, 4- NO2, 2-NHCOCH3,3- NHCOCH3, and 4- NHCOCH3
2. A claim, as claimed in claim 1, wherein the preparation of a novel compound of
formula I, which comprises of
a) reacting the diazonium salt of formula II

where X= F, Cl, Br, BF4 with the product of formula III

b) isolating the product of formula I
c) purifying the product of formula I

3. A claim, as claimed in claim 2a, wherein diazonium salt prepared in aqueous medium reacted with nitroethenamine derivative of formula III, in a aqueous organic medium at a temperature of 40 to 70 °C.
4. A claim, as claimed in claim 3, wherein the aqueous medium contains 50 - 75% of the organic solvent selected from the group dimethyl formamide, dimethyl acetamide,

N-methyl pyrolidone, dimethyl sulfoxide and solfolane either singly or in combination of two or more of the solvent.
5. A claim, as claimed in claim 3, wherein, the temperature at which addition and reaction of diazonium salt are to be made may be set within the range of 40 to 70°C, and preferably 60 to 70 °C.
6. A claim, as claimed in claim lb, wherein the product of formula I is isolated by extracting with an organic solvent like toluene xylene, ethyl acetate, chloroform or ketonic solvent.
7. A claim, as claimed in claim 2c, wherein the reaction mixture is then acidified with hydrochloric acid followed by addition of zinc dust.
8. A claim, as claimed in claim 2c, wherein the reaction mixture is then refluxed for one
hour in order to reduce any disulfide to thiol.
9. A claim, as claimed in claim 2c, wherein the content of the flask was cooled and
extracted with ether. A brown, solid tar, which was insoluble in acid, alkali or ether,
remained behind.
10. A claim, as claimed in claim 2c, wherein the brown ether extract is repeatedly washed
with 5% sodium hydroxide solution until the alkaline solution no longer turns brown,
then with dilute hydrochloric acid, water and finally dried over sodium sulfate.
11. A claim, as claimed in claim 2c, wherein after removal of ether, the remaining oil is
distilled or recrystallized to afford the 2-(2-arylthio)-2-methylamino-l-nitroethene