HU213264B - Method for producing n,n'disubstituted, 2 nitro 1,1-ethene-diamines - Google Patents

Abstract

The present invention relates to a process for the preparation of compounds of general formula (X). In which R 3 is di (C 1-4 alkyl) amino (C 1-4 alkyl) phenyl (C 1-4 alkyl) - thio (C 1-4 alkyl), and R 1 is 1 –4 carbon atoms. According to the present invention, the nitrite diacid acetic acid salt is reacted with a primary amine reagent of the general formula R1NH2, and the captured artificial salt is reacted with an alkylating agent R2-X to give an N-substituted-1-alkylthio derivative which is reacted with an amine of general formula R3NH2. In particular, histamine H2 antagonist is used to produce ranitidine. ŕ

Description

The present invention relates to a novel process for the preparation of N, N'-disubstituted-2-nitro-1,1-ethylenediamines, in particular ranitidine, from N-substituted-1-alkylthio-2-nitroethyleneamines.

Ranitidine, i.e. N- {2- / 5- (dimethylamino) methyl-2-furanylmethylthioethyl} -N'-methyl-2-nitro-1,1-ethenediamine, is known. histamine H2 antagonist.

Spanish Patent No. 523,448 describes the preparation of N-substituted-1-alkylthio-2-nitroethyleneamines, more particularly N-methyl-1-methylthio-2-nitroethyleneamines. according to the reaction scheme.

The starting material used in the reaction is the dipotassium salt of nitrodithiothioacetic acid (1-nitro-2,2-bis-mercaptoethylene) and the reaction is carried out in three steps, first by methylation with dimethyl sulfate and then with methylthiomethyl group. is converted to the amino group with methylamine, followed by further methylation with additional dimethyl sulfate.

British Patent No. 2,160,204 also discloses the preparation of N-methyl-1-alkylthio- (e.g., 1-methylthio) -2-nitroethylene amines, which include the preparation of intermediates such as alkylation (e.g., methylation) of the compound of formula (VI) above.

The three-step reaction described in the above-mentioned Spanish Patent must be carefully controlled to prevent the formation of unwanted reaction products such as bis (methylthio) derivatives. A further disadvantage of the process is that the toxic dimethyl sulfate must be repeatedly applied.

It is known that amines generally do not react with dianions because the lone electron pair present on the amine prevents reaction with molecules that already carry two negative charges. This inhibition does not apply to dimethyl sulfate. Thus, the reaction sequence of Spanish Patent No. 523,448 corresponds to the state of the art.

However, in our experiments it has surprisingly been found that certain amines can be directly reacted with nitro-dithioacetate-dianinone. This allowed the development of a highly selective two-step reaction for the preparation of amino-substituted-thio-substituted-nitroethenes. The reaction is one step less than the reaction of the above-mentioned Spanish Patent, and is advantageous because the reaction steps do not need to be controlled so strictly, there is no over-substitution during the amination and high yield of the product is obtained.

The present invention therefore relates to a process for the preparation of compounds of formula X wherein:

R ₃ is di (C 1-4 alkyl) amino (C 1-4 alkyl) furanyl (C 1-4 alkyl) thio (C 1-4 alkyl), and

R 1 is C 1-4 alkyl.

According to the present invention, the dipotassium salt of nitro-dithioacetic acid is reacted with a primary amine of formula R ₁ NH ₂ , wherein R 1 is as defined above, and the resulting compound of formula I, wherein R 1 is as described above, is an alkylating agent _R2 is C1-4 alkyl and X is a leaving group - and the compound of general formula (II) - wherein R] and _R2 are as defined above - is reacted with an amine of formula R ₃ NH 2 - wherein R ₃ represents the upper.

In a preferred embodiment of the process of the invention, dipotassium nitrodithioacetate is reacted with methylamine, wherein R 1 is methyl. This product was found to be the same as the reaction product of Step 2 of the above-mentioned Spanish Patent, which is described in more detail in Example 2, first and second paragraphs, of the above-mentioned Spanish Patent.

Other primary alkylamines useful in the process of the invention are straight-chain alkylamines such as C2-C4. In the primary alkyl amines containing a heteroatom in the chain, such a heteroatom may be, for example, a sulfur atom and the chain may be, for example, a chain of formula (a). An example of a compound containing such a chain is the compound of formula VIII, i.e., 2- [5- (N, N-dimethyl-4-aminomethyl) -2-furanomethylthio] ethylamine. It will be seen from the foregoing that the primary alkylamine containing the heteroatom may be substituted without losing the basic nature of the primary amine. The reaction according to the invention between the latter amine and dipotassium nitrodithioacetate gives a new product which can be represented by the formula (III).

The nitrate dithioacetic acid dipotassium salt which can be used as starting material is described in E. Freund, Chem. Bér. 52, 542 (1919), whereby an ethanol-wet mass is obtained. The weight given herein is taken as 100% and ethanol is treated as the solvent.

The amination reaction is preferably carried out in a polar solvent such as water, methanol, ethanol, isopropanol or dimethylsulfoxide. Water is the preferred solvent in terms of cost and handling. The concentration of the reaction mixture (ratio of water or other solvent to the dipotassium salt of nitrodithioacetic acid) is 20; It may range from 1 to 1: 1, preferably from 10: 1 to 5: 1 by weight. Concentration values are by weight unless otherwise indicated. The amine and nitric dithioacetic acid dipotassium salts in a molar ratio of 0.8: 1 to 2: 1 are economically advantageous in the amination step, and the economic ratio is preferably 1.1: 1.

The amination reaction is carried out at 0 to 100 ° C, preferably at 20 to 60 ° C.

Conversion of the thioamide salt to a thioalkyl derivative is carried out at 0 to 60 ° C, preferably at 10 to 40 ° C, so that the reaction time is optimal and the side reaction is prevented.

Suitable alkylating agents are alkyl halides or sulfates. Particularly preferred alkylating agents are dimethyl sulfate, diethyl sulfate, methyl chloride, methyl bromide and methyl iodide, of which dimethyl sulfate is particularly preferred. The alkylation reaction is preferably carried out in the presence of a phase transfer catalyst such as benzyltrimethylammonium chloride.

In the alkylation step, the alkylating agent and the dipotassium salt of nitrodithioacetic acid are in the range of 1: 1 to> 4: 1 mole2.

HU 213 264 Β, optimum yields of 2: 1 and

1.5: 1 molar ratio.

The potassium salt of formula (I) is preferably reacted in situ with the alkylating agent, in which case the reaction is usually carried out in the same solvent as the amination step.

Preferably, the process of the invention is carried out by reacting the dipotassium salt of nitro-dithioacetic acid with methylamine to give compounds of formula I wherein R1 is methyl which is methylated in situ with dimethyl sulfate such as N-methyl- 1-methylthio-2-nitroethylenamine is obtained, i.e., a compound of formula II wherein R1 and R2 are methyl.

The nitroethylene amine of formula (II) may be recovered from the reaction mixture by conventional methods, such as filtration, or more preferably, extraction with a suitable solvent, preferably a water-immiscible chlorinated solvent such as methylene chloride, ethylene chloride or chlorobenzene followed by drying and evaporation of the organic extract. If desired, the product obtained by the working-up process is recrystallized from a suitable solvent, for example propan-2-ol.

N-N'-disubstituted-2-nitro-1,1-ethylenediamines can be prepared by reacting the resulting N-substituted-1-alkylthio-2-nitroethylene amine (II) with a suitable amine in a known manner. .

In a preferred embodiment of the process of the invention, ranitidine is prepared by treating 2- [5- (N, N-dimethyl-1-methylthio-2-furanomethylthio) ethylamine as N-methyl amine. -1-methylthio-2-nitroethyleneamine as a compound of formula II.

The following examples illustrate the process of the invention.

Example 1

N-methyl-l-methylthio-2-nitro-ethene amine

129 g of the dipotassium salt of nitro-dithioacetic acid are dissolved in 560 ml of water. Then, 52 g of 40% by weight aqueous methylamine are added and the solution is stirred at 30 ° C for 6 hours to effect the formation of the 1- (methylamino) -2-nitroethylene thiopotassium salt.

The reaction mixture was cooled to 20 ° C and benzyl trimethylammonium chloride (8 g) was added followed by ca. 191 g of dimethyl sulfate were added over 1 hour. The methane thiol formed is removed in a suitable scrubber.

After stirring overnight, the resulting solid precipitate was filtered off and recrystallized from propan-2-ol to give the title compound (61 g, m.p. 110 ° C). This yield is 68.7% of the dipotassium derivative.

Example 2

N-Methyl-1-methylthio-2-nitroethenamine

After treatment overnight, the reaction mixture obtained in Example 1 was extracted with dichloromethane (3 x 100 mL). The combined organic layers were dried over magnesium sulfate, evaporated and the residue crystallized from propan-2-ol to give 76 g of the title compound, m.p. 110 ° C. This yield is 85.7% of the dipotassium derivative.

Example 3

N- {2- [5- (Dimethylamino) -2-furanyl methylthio] ethyl} -N'-methyl-2-nitro-I, l-ethenediamine

A solution of 32.1 g of 2- [5- (N, N-dimethylaminomethyl) -2-furanomethylthio] ethylamine in 25 ml of water is added dropwise over 4 hours to 23 g of N-methyl-1 -methylthio-2-nitroethyleneamine in 40 ml of water with stirring at 50 ° C. The reaction mixture was heated at 50 ° C for a further 2 hours and then heated to 90 ° C. To the solution is added 150 ml of methyl isobutyl ketone and the water is removed by azeotropic distillation. The solution was cooled to 60 'C and 1.5 g of activated carbon was added. The mixture is filtered, the carbon is washed with 50 ml of methyl isobutyl ketone, the filtrate and the washings are combined and cooled to 0 ° C. 39 g of the title product crystallize out which is filtered, m.p. 68-70 ° C.

Example 4 (Reference Example)

Potassium salt of N- {2- [5- (dimethylaminomethyl) -2-furanylmethylthio] ethyl} -1-amino-2-nitroethylene thiol (Compound III)

139 g of dipotassium nitrodithioacetate are dissolved in 560 ml of water and ca. 195 g of 2- [5- (N, N-dimethylaminomethyl) -2-furanomethylthio] ethylamine (195 g) are added. The reaction mixture was heated at 40 ° C for 2 hours, then at 60 ° C for a further 2 hours and finally stirred at room temperature overnight to give the title product. TLC (silica, 15: 5: 1 v / v 1,2-dichloroethane / methanol / acetic acid) Rf = 0.31.

Claims (6)

PATENT CLAIMS A process for the preparation of compounds of formula X wherein: R3 is di (C1 -C4 alkyl) amino (C1 -C4 alkyl) furanyl (C1 -C4 alkyl) thio (C1 -C4 alkyl), and R 1 is a C 1 -C 4 alkyl group, characterized in that the dipotassium salt of nitro-dithioacetic acid is reacted with a primary amine of formula R 1 NH 2 - where R 1 is as defined above - to give a compound of formula I with an alkylating agent R ₂ X, wherein R ₂ is C 1 -C 4 alkyl, and X is a leaving group, and the resulting compound of formula II, wherein R 1 and R ₂ are as defined above, is an R ₃ NH? with an amine of the formula wherein R3 is as defined above. Process according to claim 1, characterized in that the amine is 2- [5- (N, N-dimethylaminomethyl) -2-furanylmethylthio] ethylamine. 3. The process of claim 1, wherein the alkylation reaction is carried out on an in situ prepared compound of formula (I). 4. The process according to any one of claims 1 to 3, wherein the alkylating agent is a methylating agent. HU 213 264 Β 5. The process according to claim 4, wherein the methylating agent is dimethyl sulfate. 6. A process according to any one of claims 1 to 3, characterized in that the alkylation is carried out in the presence of a phase transfer agent.