NL194440C - - Google Patents

Description

η 1 194440

Process for the preparation of N-methyl-1-alkylthio-2-nitroethylene amine derivatives

The invention relates to a process for the preparation of a N-methyl-1-alkylthio-2-nitroethylene amine derivative of the formula 3, wherein R 1 represents a-1-alkyl group.

N-methyl-1-alkylthio-2-nitroethylene amine derivatives are useful as intermediates for the preparation of ranitidine and other histamine H 2 antagonists with a -NHC (= CHNO 2) NHCH 3 end group, such as nizatidine.

A certain type of process for preparing compounds of the formula 3 is already known. This type of process involves an ai or non-direct replacement of a single alkylthio group in 1.1-10 (bis) alkylthio-2-nitroethylene derivatives by a reaction with methylamine.

For example, U.S. Pat. No. 4,128,658 (see Example 13) describes a process for preparing N-methyl-1-methylthio-2-nitroethylene amine. This process involves the reaction of 1,1- (bis) methylthio-2-nitroethylene with methylamine. After recrystallization, the yield of the desired product is 39.4%.

German Offenlegungsschrift No. 2,621,092 also describes a process for the preparation of N-methyl-1-methylthio-2-nitroethylene amine, starting from 1,1- (bis) methylthio-2-nitroethene. in Examples 1 and 2, the 1,1- (bis) methylthio-2-nitroethylene is first partially oxidized to a monosulfoxide before reaction with methylamine and the N-methyl-1-methylthio-2-nitroethylene amine is obtained. the yield of desired product after recrystallization 54.76%.

In addition, another type of process has been calculated for preparing compounds that are similar to compounds of the formula 3. This type of process involves reacting an isothiocyanate with nitromethane in the presence of a base, followed by alkylation with an alkylating agent .

For example, British patent specification 1,421,792 describes a process for the preparation of compounds of the formula 1, wherein X and Y are the same or different and each represents hydrogen, nitro, cyano or SO 2 Ar (Ar is unsubstituted or substituted phenyl) with the proviso that X and Y do not simultaneously represent hydrogen, R is an alkyl group and R2 is an alkyl group or an aralkyl group, namely through the reactions of scheme A. According to this scheme, a substituted methane CH2 XY will react with an isothiocyanate ester after a treatment with a strong base such as sodium hydride or sodium hydroxide. In the only specific example of this reaction given, sodium hydride and dimethylformamide are converted. The second step of the reaction is carried out by adding methyl iodide to dimethylformamide.

In the preparation of 1-alkylthio-2-nitroethylene amine derivatives, however, the exemplary embodiments of British Patent Specification 1,421,792 always start from the corresponding 1,1- (bis) alkylthio-2-35 nitroethylene.

Furthermore, in Chem. Ber. 100, 591-604 (1967) describes the conversion of phenyl isothiocyanate with nitromethane. It is also described therein that the reaction must be carried out in the presence of sodium hydride in dimethylformamide. This reaction is followed by methylation with methyl iodide to give N-phenyl-1-methylthio-2-nitroethylene amine.

The use of sodium hydride in dimethylformamide as described in the references cited above in a method as described in the preamble is unsuitable for preparation on a technical scale because of the known dangers associated with the combination of these substances.

It has been found that the above-mentioned disadvantage is prevented by reacting methyl isothiocyanate with the carbanion of nitromethane in the presence of dimethyl sulfoxide as solvent in a process as described in the preamble to prepare the compound of the formula 2 in which Q represents a cation derived from a suitable base used to form the carbanion of nitromethane in situ, and then the compound of formula 2 is reacted with a suitable alkylating agent.

An advantage of the process according to the invention over a process in which dimethylformamide is used as solvent is that the use of alkali metal hydrides in dimethyl sulfoxide presents fewer dangers. Thus, the method according to the invention, which is cheaper and simpler and uses commercial starting materials, can generally be carried out safely on a technical scale and under mild conditions.

Another advantage is that the process according to the invention provides compounds of the formula 3 in a relatively high yield. Thus, when the reaction of methyl isothiocyanate with nitromethane is carried out in the presence of sodium hydride as the base, the yield increases from 22% using 194440 dimethylformamide as a solvent to 59% using dimethyl sulfoxide as a solvent. Furthermore, in the process according to the invention, the compounds of the formula 3 are obtained in a form which can be used without further purification to prepare compounds such as ranitidine.

It is noted that the use of dimethyl sulfoxide in nucleophilic conversions with compounds containing an activated carbon-hydrogen bond is described in the book "dimethyl sulfoxide" by D. Martin and HG Hauthal (Akademie-Verlag, Berlin), 1971, p. 174 -177, 197-198 and 226-233.

According to Chemical Abstracts 79, 41826y (1973), in the reaction of 1,1- (bis) methylthio-2-nitroethylene with compounds containing an active methylene group using dimethyl sulfoxide as the solvent and sodium hydroxide as the base, only one of the two replace methylthio groups.

Nonetheless, in the aforementioned German "Offenlegungsschrift" 2,621,092, when searching for an improved process for preparing 1-alkylthio-2-nitroethylene amine derivatives, there is no attention to the conversion of a suitably substituted isothiocyanate with nitromethane in dimethyl sulfoxide in the presence of a base.

Knowing the beneficial properties of dimethyl sulfoxide in the nucleophilic reactions with compounds containing an activated carbon-hydrogen bond, one skilled in the art therefore has no reason to assume that N-methyl-1-alkylthio-2-nitroethylene amine derivatives of the present formula 3 may be suitable are prepared by reacting methyl isothiocyanate with the carbanion of nitromethane in the presence of dimethyl sulfoxide and then reacting the resulting compound of the present Formula 2 with an appropriate alkylating agent.

In the method according to the invention, the carbanion of nitromethane is prepared in situ by treatment of nitromethane with an appropriate base. Particularly suitable bases include alkali metal hydrides, alkali metal hydroxides or alkali metal alkanolates, for example sodium hydride, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium isopropoxide, and potassium t-butoxide.

When the base is an alkali metal hydroxide, it can be added in the form of an aqueous solution.

In the process according to the invention, a co-solvent may be present in addition to the dimethyl sulfoxide. Suitable auxiliary solvents, the choice of which depends on the base used, include aprotic solvents (such as dimethylformamide and N-methylpyrrolidone) and water.

The compound of formula 2, wherein Q represents a cation, can be treated with a suitable alkylating agent, such as an alkyl halide (for example methyl bromide or methyl iodide) or a dialkyl sulfate (for example dimethyl sulfate) to give an N-methyl-1-alkylthio-2 - nitroethylene amine derivative of the formula 3, wherein R 1 is a C 1-4 alkyl group.

When the follow-up reaction with the alkylating agent is carried out on a compound of the formula 2 prepared in situ, then usually the solvent medium used in the alkylation reaction will be the same as that used in the first reaction.

The reaction temperature is usually between 0 and 50 ° C; most preferably the reaction is carried out at room temperature.

A particular embodiment of the process according to the invention comprises the methylation of the compound of the formula 2 obtained in situ, using an appropriate methylating agent such as methyl iodide or dimethyl sulfate, to form the N-methyl-1-methylthio-2-nitroethylene amine, namely, the compound of formula 3 wherein R 1 represents methyl.

The compound of the formula 2, wherein Q is hydrogen, can be prepared from the compound of the formula 2, wherein Q is a cation, namely by adding one equivalent of a suitable acid.

The compounds of the formula 2 can exist in tautomeric forms and the formula 2 comprises all of these 45 forms.

Histamine H 2 antagonists with a -NHC (= CHNO 2) NHCH 3 end group can be prepared by reacting an N-methyl-1-alkylthio-2-nitroethylene amine derivative of the formula 3 with an appropriate amine.

Thus ranitidine can be prepared from 2- [5- (N, N-dimethylaminomethyl) -2-furanmethylthio] ethylamine as the amine, using N-methyl-1-methylthio-2-nitroethylene amine as a compound of formula (III).

This reaction can be carried out in a solvent such as water, with or without heating. A process for the preparation of ranitidine starting from N-methyl-1-methylthio-2-nitroethylene amine is described in Example 13 of the aforementioned U.S. Patent No. 4,128,658.

The invention is illustrated by the following examples, which are not limitative.

£ 3 194440

, Example I

N-methyl-1-methylthio-2-nitroethenamine 1. 1.25 g of Nitromethane was added in one minute to a suspension of 1.15 g of potassium hydroxide flakes in 18 cm 3 of dimethyl sulfoxide containing 7.5% water. A solution of 1.5 g of methyl isothiocyanate in 2.5 cm 3 of dimethyl sulfoxide (with 7.5% water) was added over 2 minutes, keeping the temperature at 20-26 ° C. This solution was stirred for a further half an hour at room temperature, after which 3.19 g of methyl iodide was added dropwise over 2 minutes, keeping the temperature at 22-24 ° C. After stirring an additional 1 hour at room temperature, the solution was diluted with 200 cm 3 of water and extracted with dichloromethane. The combined extracts were washed with water and then evaporated to dryness and the residue was recrystallized from 2-propanol to give 1.5 g of the title compound; yield 49.4%; m.p. 113-116 ° C.

2. 1.32 g of nitromethane in 5 cm 3 of dimethyl sulfoxide containing 7.5% of water was added over 5 minutes at 0-5 ° C to 0. 52 g of sodium hydride in 20 cm 3 of dimethyl sulfoxide (with 7.5% water). This mixture was allowed to come to room temperature and after a further 30 minutes, 1.58 g of methyl isothiocyanate in 5 cm 3 of dimethyl sulfoxide containing 7.5% of water was added in 5 minutes. The mixture was then reacted with 3.07 g of methyl iodide in 5 cm 3 of dimethyl sulfoxide containing 7.5% water, keeping the temperature below 30 ° C, and the resulting solution was stirred overnight. The solvent was removed, 50 cm 3 of water was added to the residue and the mixture was worked up according to the general procedure of Example 1 (1), whereby 1.88 g of the title compound were obtained; yield 58.7%; M.p. 112-114 ° C.

3. 0.62 g of nitromethane was added dropwise over 2 minutes to a suspension of 1.1 g of potassium t-butoxide in 9 cm 3 of anhydrous dimethyl sulfoxide under a nitrogen atmosphere at a temperature of 20-25 ° C. This mixture was stirred for 10 minutes and a solution of 0.715 g of methyl isothiocyanate in 3 cm 3 of dimethyl sulfoxide (containing 7.5% water) was added dropwise in 2 minutes. After stirring for another half hour at room temperature, 1.52 g of methyl iodide was added dropwise over 2 minutes, keeping the temperature at 20-25 ° C. This solution was stirred at room temperature for 2 hours, diluted with 100 cm 3 of water and worked up according to the procedure of Example 1 (1) to 0.96 g of the title compound; yield 66.1%; m.p. 113-115.5 ° C.

4. According to the procedure of Example 1 (3), but using 1.6 g of sodium hydroxide instead of the potassium t-butoxide, 2.44 g of nitromethane in 35 cm 3 of dimethyl sulfoxide with 7.5% water, and 2.92 g of methyl isothiocyanate converted to 5 cm 3 of dimethyl sulfoxide containing 7.5% water, followed by an alkylation with 6.25 g of methyl iodide to give 2.64 g of the title compound; yield 44.5%; m.p. 113-116 ° C.

Example II

N-methyl-1-methylthio-2-nitroethylene amine 20.88 g of potassium hydroxide and 12.4 cm 3 of water were added to a stirred solution of 27.22 g of methyl isothiocyanate and 22.75 g of nitromethane in 185 cm 3 of dimethyl sulfoxide, the temperature being 10 -15 ° C. Stirring was continued for 60 minutes at 10-15 ° C, after which the solution was divided into two equal parts of 120 cm3 each.

1. The first portion was stirred at 10-15 ° C while 17.62 cm 3 of dimethyl sulfate was added over a 15 minute period. Stirring was continued for 30 minutes, after which 90 cm 3 of water were added and the mixture worked up according to the procedure described in Example 1 (1), to yield the title compound in an amount of 12.45 g, yield 45.1%, and 45 a melting point of 112.5-114 ° C.

2. The second part was treated with 11.66 cm 3 of methyl iodide and worked up in the same manner to yield 14.61 g of the compound mentioned in the preamble, with a yield of 52.9%. The melting point was 112.5-114 ° C.

Example III

N-methyl-1-methylthio-2-nitroethylene amine 1.05 g of nitromethane and 1.26 g of methyl isothiocyanate in 6.71 g of anhydrous dimethyl sulfoxide was added over 70 minutes to a stirred suspension of 0.41 g of sodium hydride in 4.3 cm3 of dimethylformamide wherein the temperature was kept below 25 ° C. Stirring was continued for 3 hours, after which 2.45 g of methyljo-55 dide was added over 15 minutes while the temperature was kept below 30 ° C. The resulting solution was stirred for 30 minutes, 9 cm 3 of water was added and the solution was worked up according to Example 1 (1) to the title compound (1.30 g); yield 50.8%, m.p. 113-115.5 ° C.

Claims (1)

Process for preparing an N-methyl-1-alkylthio-2-nitroethyleneamine derivative of the formula 3, in which R 1 represents a C 1-4 alkyl group, characterized in that methyl isothiocyanate is reacted with the carbanion of nitromethane in the presence of dimethyl sulfoxide as a solvent, so that the compound of formula 2 is prepared, wherein Q represents a cation derived from a suitable base used to form the carbanion of nitromethane in situ, and then the compound of formula 2 is reacted with a suitable alkylating agent. Hereby 1 sheet drawing