CS248717B2 - Production method of the hydrochloride of the 1-(2-(5 dimethylamino-methyl-2-furylmethylthio)ethyl)p)amino-1-methylamino-2-nitroethylene - Google Patents

Abstract

The invention relates to a process for preparing the hydrochloride of 1-(2-(5-[dimethylaminomethyl]-2- [furylmethylthio]ethyl))amino-1-[methylamino]-2- nitroethylene of the formula I and is characterized in that the hydrochloride of 5-[dimethylaminomethyl]furfuryl alcohol of the formula IV is reacted with cysteamine hydrochloride at temperatures between 50 degree C and 100 degree C in the absence of solvents - preferably in the presence of a catalytic amount of from 10 to 20 mol% of mineral acid and, where appropriate, in the presence of 5 to 10 mol% of an organic acid with a pKa of 0 to 2 or in the presence of a catalytic amount of 2 to 10 mol% of amounts, which are catalytic under the reaction conditions, of mineral acid, and possibly compounds which release organic acids with a pKa of 0 - 2, the dihydrochloride, formed in this way, of the base of the formula II is removed and the monohydrochloride of the base of the formula II is liberated therefrom with an inorganic base and is - where appropriate after intermediate isolation - reacted with 1-[methylthio]-1- [methylamino]-2-nitroethylene of the formula III at temperatures between 40 degree C and 80 degree C, and the hydrochloride thus obtained, of the base of the formula I is removed.

Description

The present invention relates to a novel process for the preparation of 2- (furylmethylthto) ethyl] amino-1-methylhydrochloride of 1- {2- [5-dimethylaminomethylamino-2-nitro-ethylene of formula I

H ₃ C H ₂ __ ^V JIqK C-CH = CH-NH-C-NH-C ^ ^н / ^CH-N ° Z (0 and optionally converting that compound in the base of formula I. The invention also relates to novel key intermediates for the preparation of the abovementioned compounds, namely the novel dihydrochloride and 2 - [(2-aminoethyl) thiomethyl] -5'-dimethylaminomethylfuran monohydrochloride of the formula II

The compound of formula I is a selective histamine H-2 receptor antagonist compound and can therefore be used as an excellent drug against gastric and duodenal ulcers. For therapeutic purposes, the compound of formula I is used in the form of the hydrochloride.

The following procedures have been described in the literature for the preparation of the hydrochloride of the compound of formula (I):

a) According to Example 32 of German Offenlegungsschrift 2,734,070, the hydrochloride of the compound of formula I is prepared by dissolving the base of formula I in ethanol and precipitating the resulting hydrochloride by addition of ethyl acetate to give the hydrochloride in a yield of 89.6% based on the amount by weight of the base used as the starting compound.

According to Belgian Patent Specification No. 890,574, the hydrochloride of the compound of formula (I) thus obtained is poorly filtered and dried and is therefore not suitable for large-scale production.

b) According to Example 1 of Belgian Patent Specification 890 574, the hydrochloride of the compound of formula I is prepared by adding concentrated aqueous hydrochloric acid to a solution of the base of formula I in aqueous isopropanol and precipitating the resulting hydrochloride by adding an additional portion of isopropanol to yield the hydrochloride in 93. 9% based on the weight of the base.

Thus, in both processes described, the starting material is a base of formula I. Therefore, taking into account the prior art known processes for the production of hydrochloride, the base of formula I should first be prepared in a quality suitable for the preparation of the hydrochloride.

For the synthesis of the base of formula (I), three methods are described in the above-mentioned German Published Patent Publication No. 2,734,070 (Examples 15, 20 and 21). Of these methods, the procedure described in Example 15 is most acceptable in view of the result; according to this process, the base of formula I is prepared by treating the base of formula II with 1-methylthio-1-methylamino-2-nitroethylene of formula III

H3C — S \

C = CH-NO 2

OF

HsC-NH [III] for about 8 hours in the presence of water. The base of the formula I having a melting point in the range of 69 to 70 ° C is obtained in a yield of 78%, based on the weight of the compound of the formula II. A significant drawback of this disclosure is that it does not provide precise conditions for recrystallization, although these conditions are critical to both the yield and the quality of the base of Formula I.

Examining this reaction, it has been found that the process described in Example 15 does not give a base of formula I in a quality that allows the production of hydrochloride by an industrial process and satisfies the requirements for the preparation of pharmaceutical compositions.

The difficulties associated with the preparation of the base of formula I and its hydrochloride suitable for pharmaceutical compositions as well as the lack of a satisfactory solution to this problem are also evidenced by the fact that a number of other proposals have been made regarding the preparation of these compounds, such as disclosed in British patent 2,075 980, Belgian patents 886 997 and 890 574, Spanish patents 495 493, 497 386, 497 737, 502 940, 504 461, 507 360, 508 693, 511 830 and 512 315, as well as published European patent applications No. 55,625,555,626, 59,082 and 64,869. However, the processes to which these patents and patent applications relate do not provide a satisfactory solution to the drawbacks associated with the large-scale production of the hydrochloride of the base I.

It is therefore an object of the present invention to provide a process for the preparation of a compound of formula I and its hydrochloride, which makes it possible to produce these compounds in good yield and on an industrial scale in a simple manner.

Surprisingly, it has now been found that the above-mentioned drawbacks can be overcome by reacting the monohydrochloride of the base of formula II, instead of the base of formula II only, as the starting material with the compound of formula III. It has further been found that by using the monohydrochloride of the base of formula II as the starting material, the hydrochloride of the compound of formula I suitable for pharmaceutical compositions can be obtained directly.

This finding could not be expected for several reasons. First, according to the above-mentioned DOS file no. No. 2,734,070, by reacting a base of a compound of formula II with a compound of formula III to obtain a base of formula I, on the one hand, it is known that displacement of a methylthio group with amines such as amines in the form of hydrohalide salts (Houben-Weyl: Methoden der Organischen Chemie, ed. E. Müller, Vol. IX, Georg Thieme, Stuttgart, 1955, p. 757 and especially p. '758; Example 1 of British Patent No. 2,038,322. Finally, on the basis of the known methods known to date, the reaction of the monohydrochloride of the base of the formula II with the compound of the formula III 'could not be expected to directly lead to the preferred hydrochloride of the compound of the formula I.

The compound of formula III used in the process of the invention is known from the literature (British Patent No. 2,075,960, p. 3, Example 1).

The monohydrochloride of the base of formula II used in the process of the invention is a novel compound which, prior to its reaction with a compound of formula III, can be prepared in good yield either separately or in situ from the novel dihydrochloride of the base of formula II or base of formula II. The invention also provides the preparation of these novel hydrochloride salts of the base of formula II.

It has been found that these compounds can be prepared very advantageously by reacting 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride of formula IV

H.C /

^H ₃ ^X p. hydrochloride. cysteamine.

The present invention therefore provides a novel process for the preparation of 1- (2- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl] [-amino-1-methylamino-2-nitroethylene hydrochloride of formula I)

N - HAC -. θ ^Η

(I) and optionally converting the hydrochloride into a base of formula I, characterized in that the hydrochloride of 5-dimethylaminomethyl-2-furfuryl alcohol of formula IV

is reacted with cysteamine hydrochloride at a temperature in the range of 20 to 120 ° C, optionally with the addition of an inert organic. a diluent, in the presence of a catalytic amount of a mineral acid and optionally an organic acid having a pKa value of 0 to 2, or in the presence of a catalytic amount of a substance providing a mineral acid and optionally an organic acid having a pKa value of 0 to 2 under the above conditions; base of formula II

N-H 3 C S - (CH ₂ ) 3 NH ₂

And / or releasing the monohydrochloride of the base of formula II and reacting, optionally without isolation, with 1-methylthio-1-methylamino-2-nitroethylene of formula III

CHg — S \

C = CH — NO2

OF

CH 2 -NH (ΠΙ) and optionally the base hydrochloride of formula I formed by one of the above processes is isolated and purified, and / or optionally liberates the base of formula I and / or optionally purifies and transforms it into its hydrochloride.

An embodiment of the process according to the invention consists in reacting the hydrochloride of the compound of formula IV with cysteamine hydrochloride in the presence of a catalytic amount of a mineral acid, preferably hydrochloric acid, without adding a solvent, optionally in the presence of an inert organic diluent. This reaction is carried out at a temperature in the range of 20 to 120 ^° C, preferably 20 to 75 ° C. Part of the catalytic amount of the mineral acid may be replaced by an organic acid of similar strength (pKa value of 0 to 2), preferably by a sulfonic acid, for example p-toluenesulfonic acid.

The dihydrochloride salt produced by the process of the invention may be isolated by a known method, for example by addition. a lower alcohol, such as ethanol, or a mixture of a lower alcohol with a lower aliphatic ketone, such as acetone, to a cooled reaction mixture, thereby precipitating the dihydrochloride of the base of formula II mostly in crystalline form and can be isolated by filtration.

In this way, the dihydrochloride of the base of formula II can be obtained in a yield of, for example, 87%.

The free base of formula II can be liberated from its dihydrochloride obtained by the above reaction, either in situ or after isolation of the dihydrochloride, by addition of a suitable base such as an alkali metal hydroxide to the dihydrochloride. From this base, the monohydrochloride can be prepared in a known manner. Alternatively, however, the dihydrochloride salt of the base of formula II obtained by the process of the invention can be converted into the monohydrochloride of the base of formula II directly without releasing the base. From the monohydrochloride thus obtained, 1- [2- [5-dimethylaminomethyl-2- (lurylmethylthio) ethyl]] - amino-1-methylamino-2-nitroethylene hydrochloride (I) may be prepared.

In the process of the invention, a catalytic amount of a substance providing a mineral acid or mineral acid and an organic acid of similar strength to that of a mineral acid, preferably a phosphorus halide (e.g. phosphorus oxychloride) or a halide, is added to the mixture of the hydrochloride of the compound IV with cysteamine hydrochloride. organic or inorganic acids (such as thionyl chloride, p-toluenesulfonyl chloride) or aluminum chloride, whereupon the reactants are reacted for 2 to 3 hours at a temperature ranging from 50 to 90 ° C in the absence of any solvent. In this way, the dihydrochloride of the base of formula II can be obtained in a yield of 82-92%.

Optionally, the process of the invention can condense the hydrochloride salt of the compound of formula IV with cysteamine hydrochloride in the presence of an inert organic diluent in which none of the starting hydrochlorides is dissolved. The use of such diluents can be particularly advantageous when the process of the invention is applied for large-scale production. Suitable diluents are aliphatic, aromatic or halogenated aliphatic hydrocarbons. For this condensation reaction, benzene, toluene, dichloroethane or petroleum ether (boiling in the range of 60-100 ° C) may be used as the diluent.

From the base dihydrochloride II thus obtained, the base monohydrochloride II can be prepared and reacted with 1-methylthio-1-methylamino-2-nitroethylene III as described above.

The reaction mixture obtained in the process according to the invention essentially comprises a base hydrochloride of the formula I, which crystallizes from the reaction mixture, optionally after addition of a suitable solvent or solvent mixture, such as aqueous ethanol or a mixture of ethanol and acetone, to the reaction mixture.

The purity of the hydrochloride of the base of formula I prepared by the process according to the invention is at least -95%. This product can optionally be further purified by chromatography and / or fractional crystallization.

The 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride of formula IV used in the process of the invention is a known compound [J. Am. Chem. Soc., 89, p. 464 (1947)]. Cysteamine hydrochloride is available commercially.

The advantages of the process according to the invention can be summarized as follows:

If the purpose is to prepare the hydrochloride of the base of formula I, it is not necessary to prepare and - isolate the base of formula I in a separate step to form the hydrochloride. This is particularly advantageous since the preparation of the base of formula I in pure crystalline form is problematic by the prior art.

Using the process according to the invention, the hydrochloride of the base of formula I is obtained directly in the preferred crystalline form.

The process according to the invention does not impose great demands on the volume of the production equipment, since no solvent is added to the reactants.

In view of this, the process of the invention is advantageous for the simple preparation of the base of formula I and its hydrochloride in good yield and on an industrial scale.

The novel dihydrochloride of the base of formula II prepared by the process of the invention is a well-defined, stable compound which can be stored unchanged and from which, at any time, suitably shortly before use, the base of formula II or a new monohydrate thereof can be prepared.

The process according to the invention is illustrated in more detail by the following examples, to which the scope of the invention is not limited in any way.

Example 1

Preparation of 2- [- (2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride (dihydrochloride base of formula II)

A mixture of 9.08 g (0.08 mol) of cysteamine hydrochloride with 15.32 g (0.08 mol) of 5 - (R, R < 1 &gt; -yl) amine &lt; 1 &gt; The irfuryl alcohol is reacted with stirring at 70-75 ° C, then 0.75 ml of concentrated hydrochloric acid is added and the mixture is stirred for one hour at 80 ° C and then for 20 minutes at 90 ° C under slightly reduced pressure ( After cooling to 70 DEG C., 15 ml of anhydrous ethanol are added and the reaction mixture is left at room temperature for 2 hours, then 15 ml of anhydrous acetone are added at 244717. The mixture is left at 0 to 4 ° C through The precipitated crystals were collected by filtration, washed with 1: 1 ethanol: acetone and dried to give 20.19 g (87.2% yield) of the title compound, mp 160-162 ° C.

Example 2

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

A mixture of cysteamine hydrochloride (14.7 g, 0.13 mol), 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (23.0 g, 0.12 mol) and concentrated hydrochloric acid (5 ml) was heated at 60 DEG C. for a few minutes with stirring. C. After about 10 minutes, the mixture was melted, the melt allowed to cool to room temperature, then stirred for 6 hours at room temperature and then allowed to stand at this temperature for 60 hours. The crystal mixture is then suspended in 100 ml of ethanol, dissolved by heating to boiling, the solution is cooled rapidly with stirring and left at a temperature between 0 and 5 ° C for 1 hour. After filtration, the product was washed with ice-cold ethanol and dried to give 25 g (72.5% yield) of the title compound which, after recrystallization from 96% ethanol, had a melting point of 163-165 ° C.

Example 3

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

A mixture of cysteamine hydrochloride (19.0 g, 0.167 mol) with 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (32.0 g, 0.169 mol) was melted by heating at 67 ° C and 1.0 ml of concentrated hydrochloric acid was added. The temperature was raised to 90 ^° C over 16 minutes and an additional 0.5 mL of concentrated hydrochloric acid was added. The mixture is left at this temperature for 40 minutes, then cooled to 80 ° C and 95 ml of anhydrous ethanol are added. The crystal mixture was stirred vigorously, cooled, filtered, washed with anhydrous ethanol and dried to give 40.1 g (yield - 83.7% based on cysteamine hydrochloride) of the title compound, m.p. 159-161 ° C. .

Example 4

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

A mixture of cysteamine hydrochloride (29.4 g, 0.26 mol) with 5'-Methylaminomethyl-2-furfuryl alcohol hydrochloride (45.96 g, 0.24 mol) was melted while heating in a water bath at 70-75 ° C with stirring. After DOML anhydrous ethanol and the mixture to cool at 40 ^E C. After 60 ml of acetone, the reaction mixture hours at room temperature, seeded internal temperature of 60 ° C (about 30 minutes) was added over 10 minutes to the reaction mixture 3.6 ml The mixture was heated at 60 ° C for 3 hours and at 70 ° C for 1 hour with stirring. 60 is then added and the mixture is stirred for 2 hours and left overnight at 5-10 ° C. The precipitated crystals are filtered, washed with ethanol and acetone and air dried to give 55.4 g (yield 80.4%) of the title compound, m.p. 158-160 ° C.

Example 5

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

A mixture of 9.08 g (0.08 mol) of cysteamine hydrochloride, 15.32 g (0.08 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride and 1 ml of water is heated with stirring at 30 ° C until a homogeneous melt is formed. 0.6 ml of concentrated hydrochloric acid and 0.5 ml of ethyl chlorosulphite solution, prepared as described below, are added over 10 minutes. The mixture was then stirred at 60 ° C for 3 hours and at 70 ° C for 1 hour. 20 ml of anhydrous ethanol are added. The mixture was allowed to cool to 40 ° C, 20 ml of acetone was added, and the mixture was stirred at room temperature for 2 hours, then allowed to stand overnight at 5-10 ° C. Further work-up of the mixture of Example 4 yields 19.48 g (84.8% yield) of the title compound, m.p. 158-160 ° C.

The ethylchlorosulfite solution is prepared by dropwise addition of 2.8 ml of thionyl chloride to 10 ml of anhydrous ethanol, maintained at -20 ° C, and then stirred at -10 ° C for 30 minutes.

Example 6

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

A mixture of 4.54 g (0.04 mol) of cysteamine hydrochloride 7.66 g (0.04 mole) of 5-dimethylaminomethyl-2-furfuryl alcohol is melted by heating at 70 to 75 ^Q C with stirring, whereupon 0 18 ml of concentrated hydrochloric acid. After heating to 80 ° C, 0.5 g of p-toluenesulfonic acid is added and the mixture is stirred at 80 ° C for 1 hour and at 90 ° C for 20 minutes under slightly reduced pressure (40-60 kPa). After cooling, the reaction mixture was treated with the procedure of po248717 described in Example 1 to give 9.83 g (yield 85.4%) of the title compound, m.p. 158-160 °.

Celsius.

Example 7

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

The procedure was as described in Example 6 except that 0.3 ml of 85% phosphoric acid was used instead of p-toluenesulfonic acid. 9.8 g (85.3%) of the title compound of melting point 158 DEG-160 DEG C. are obtained.

Example 8

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

A mixture of 9.08 g (0.08 mole) of cysteamine hydrochloride with 15.32 g (0.08 mole) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride was melted by heating at 78 ° C, and 0.2 ml of thionyl chloride was added to the melt. and the mixture is stirred at 80 ° C for 10 minutes, then at 80 ° C for 50 minutes and at 90 ° C for 20 minutes under slightly reduced pressure. After cooling to 70 ° C, 20 ml of anhydrous ethanol are added, the mixture is heated to boiling, an additional 20 ml of anhydrous ethanol and 40 ml of acetone are added and the mixture is left overnight at 5 ° C. The precipitated crystals were filtered, washed with 1: 1 ethanol: acetone and dried to give 19.6 g (85.3% yield) of the title compound, m.p. 156-158 ° C.

Example 9

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

Using the procedure described in Example 8, but using 1 g of aluminum chloride instead of thionyl chloride, 21.1 g (91.9 percent yield) of the title product were obtained.

Example 1 a d 10

Preparation of 2 - {(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

A homogeneous mixture of 95.75 g (0.5 mol) of 5-dimethylaminomethyl-2-furfuryl hydrochloride, 64 g (0.52 mol) of cysteamine hydrochloride (92%) and 9.3 ml of concentrated hydrochloric acid is stirred for 4 hours in the presence of 250 ml. ml benzene at 60-62 ° C. Then benzene was decanted and the residue was stirred for several min and taken with 235 ml of anhydrous ethanol in a water bath at 80 ^Q C. After the addition of 235 ml of acetone was stirred and then left overnight at 0-4 ° C. The separated crystals were filtered, washed and dried to give 124.5 g (86.7% yield) of the title compound, m.p. 161-164 ° C.

When 3.8 g of this product is recrystallized from 6 ml of ethanol and 6 ml of acetone is added while cooling, 3.59 g of a sample of analytical purity and melting point 163-166 ° C is obtained.

Example 11

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

The procedure was as described in Example 10 except that dichloroethane was used as the diluent instead of benzene and the mixture was stirred at boiling point for 3.5 hours. The title compound is obtained in a yield of 89% and has a melting point of 157-161 ° C.

Example 12

Preparation of 2 - ((2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride

The procedure was as described in Example 10, except that instead of benzene, petroleum ether having a boiling point in the range of 70 to 80 ° C was used as the diluent. The title compound is obtained in a yield of 83% and has a melting point of 160-162 ° C.

Example 13

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran (base of formula II) from its dihydrochloride

To a mixture of 38.6 g (0.134 mol) of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride with 19 ml of water is added 29 ml of 40% sodium hydroxide solution and the liberated base is extracted 3 times with 30 ml of ethyl acetate. The organic extracts were combined, dried over anhydrous potassium carbonate, filtered and the solvent was evaporated. The residue was distilled under reduced pressure in a Vigreux deflector column. The title compound was obtained in a yield of 79.4% (22.88 g). Its boiling point at 13.3 Pa is between 116 and 120 ° C.

Preparation 14

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethyriurane monohydrochloride (base monohydrochloride of formula II)

To a suspension of 2.87 g (0.01 mol) of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran dihydrochloride in 25 ml of anhydrous ethanol, a solution of 1.0 g (0.01) is added under stirring at 20 ° C. mole] of potassium bicarbonate in 4 ml of water, stirred for 30 minutes, the precipitated potassium chloride is filtered off and the solution is evaporated to dryness, the residue is triturated with ether, filtered, washed with ether and dried to give 2.42 g (yield 96). %] of the title compound, m.p. 115-116 ° C.

Example 15

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran monohydrochloride

A solution of 21.4 g (0.1 mol) of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran in 50 ml of methanol was added dropwise to a solution of 28.7 g (0.1 mol) of 2 - [(2-dihydrochloride) dihydrochloride. -aminoethyl) thiomethyl] -5-dimethylaminomethylfuran in 300 ml of methanol, stirred for 10 minutes, evaporated to dryness under reduced pressure, and the residue triturated with 100 ml of ether, left at 0-4 ° C for 2 hours, filtered The product was washed with ether and dried at 20 ° C to give 48 g (89% yield) of the title product, mp 111-112 ° C.

Example 16

Preparation of 1- [2- [5-Dimethylaminomethyl-2- (phenylmethyl) thio] ethyl]} amino-1-methylamino-4-nitroethylene hydrochloride (base hydrochloride of formula 1)

A mixture of 12.54 g (0.05 mol) of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran monohydrochloride, 7.41 g (0.05 mol) of 1-methylthio-1-methylamino-2-nitroethylene and 2 The reaction mixture was dissolved in 70 ml of ethanol, clarified with activated charcoal, then with Hyflo filter aid, and the pH of the filtered solution was adjusted by adding concentrated aqueous solution. hydrochloric acid to ·5, then the solution is cooled to 0 ° C, seeded and stirred at 0 ^° C for several hours, then left overnight at 0 to 4 ° C. The precipitate formed is filtered off, washed with anhydrous ethanol. and dried at 50 ° C under reduced pressure to give 6.1 g (34.8%) of the title product, m.p. 139-141 ° C.

An additional 3.8 g (21.7%) of the product of similar quality was obtained from the mother liquor with a melting point of 139-141 ° C.

Example 17

Preparation of 1- [4- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl] amino-1-methylamino-2-nitroethylene hydrochloride

To 2.87 g (0.01 mole) of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuranate dihydrochloride was added a solution of 1.0 g (0.01 mole) of potassium bicarbonate in 4 ml of water. 1.52 g (0.0102 mole) of 1-methylthio-1-methylamino-2-nitroethylene was added to the stirring mixture for 1 hour, the mixture was stirred at 40 to 50 ° C for 1 hour and then heated to 60 ° C for 10 minutes. The reaction mixture is stirred at 70 DEG C. for 1 hour and then at 70 DEG C. After cooling, 30 ml of anhydrous ethanol are added, the precipitated potassium chloride is filtered off and the filtrate is evaporated to dryness under reduced pressure. ml of 96% ethanol, the pH of the solution was adjusted to 5.5 by the addition of a few drops of aqueous concentrated hydrochloric acid, and the solution was then stirred at 0 ° C for 3 hours, then left at 0-4 ° C overnight. The precipitate formed is filtered off and worked up as described in Example 16 to give 1.77 g (50.5% yield) of the title compound, m.p. 138-140 ° C.

An additional 0.19 g (5.4%) of the product with a melting point of 138-140 ° C is obtained from the soda lye.

Example 18

Preparation of 1- [4- (4-dimethylaminomethyl-2- (methylmethylthio) ethyl]]} amino} -1-methylamino-2-nitroethylene hydrochloride

To 14.35 g (0.05 mol) of dihydrochloride

A solution of 5.0 g (0.05 mol) of potassium hydrogencarbonate in 20 ml of water was added to 2-amino (2-aminoethyl) trifluoromethylfuran. The mixture was stirred for 10 minutes, then 7.45 g (0.05 mol) of 1-methylth-1-methyl-amino-2-nitroththyl was added, the mixture was stirred at 40-50 ° C for 1 hour, over 10 minutes. The mixture was heated to 60 ° C, stirred for 1 hour and then at 70 ° C for 30 minutes. The reaction mixture is diluted with 30 ml of water, the pH of the solution is adjusted to 5 by addition of a 2N aqueous hydrochloric acid solution and extracted twice with 30 ml of chloroform each. The pH of the aqueous layer was adjusted to 10 by the addition of 2 N aqueous potassium hydroxide solution, and the reaction mixture was then extracted 4 times with 30 ml of chloroform each. The combined organic phases were dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in 70 ml of anhydrous ethanol and clarified with activated carbon first, then using the Hyflo filter aid. To the filtrate was added dropwise aqueous koncentro24 tub 3 7 17 hydrochloric acid to adjust the pH between 5.5 to 6 .načež the mixture is stirred, optionally after inoculation, 3 hours at 0 ^Q C then left overnight at 0 to 4 ° C. The precipitate was filtered off and worked up as described in Example 16 to give 7.1 g (39 percent yield) of the title compound, mp 139-141 ° C.

From the mother liquor gave an additional 3.5 g (19%) of product is obtained, melting at 139-141 C. ^Ol

Example 19

Preparation of 1- [2- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl] jammo-1-methylamino-2-nitroethylene hydrochloride

2 - [(2-Aminoethyl) thiomethyl] -5-dimethylaminomethylfuran monohydrochloride, prepared in situ in an amount of 0.01 mol, as described in Example 17, is mixed with

1.48 g (0.01 mole) of 1-methylthio-1-methylamino-2-methyl-ethylene was added and the mixture was stirred at room temperature for 8 hours, then left at room temperature for 14 hours and then stirred at the same temperature for 1 hour. . After addition of 40 ml of water, the pH of the solution is adjusted to 5 by the addition of 2 N hydrochloric acid, the mixture is extracted 3 times with 10 ml of chloroform each and then added. The pH of the aqueous phase was adjusted to 10 'by the addition of 2 N aqueous potassium hydroxide solution, and the reaction mixture was then extracted 4 times with 20 ml of chloroform each. The combined organic phases were dried and evaporated under reduced pressure. The crude base residue was dissolved in 4 volumes of anhydrous ethanol, clarified and filtered. The pH of the ethanolic solution was adjusted to 5 by addition of aqueous concentrated hydrochloric acid / at 0 ° C. The solution was then seeded, stirred at 0 ° C for 3 hours and left at 0-4 ° C overnight. The precipitate formed is filtered, washed with ethanol and dried to give 1.05 g (29.9% yield) of the title compound, m.p. 139-141 ° C.

An additional 0.9 g (26%) of the product is obtained from the mother liquor, m.p. 138-140 ° C.

The crude base of formula (I) obtained as described above may be used. to produce a crystalline product in a known manner, for example by recrystallization from 4-methyl-2 -penepanone, which then has a melting point in the range of 67 to 68 cc.

Claims (3)

A process for the preparation of 1- {2- [5-dimethylaminomethyl-2- (furylmethyl-) OF THE INVENTION thio) ethyl] jamino-1-methylamino-2-nitroethylene of formula I , and optionally converting this. hydrochloride in the base of the formula I, characterized in that the hydrochloride of 5-dimethylaminomethyl-2-furfuryl alcohol of the formula IV is present in the presence of a catalytic amount providing mineral acid and optionally an organic acid having a pKa of 0-2. the resulting dihydrochloride of the base of formula II H3C. ..... 3 ₄ j; .......-; j 'Μ- · -1. z is reacted with cysteamine hydrochloride at a temperature in the range of 20 to 120 ° C, optionally with the addition of an inert organic diluent, in the presence of a catalytic amount of a mineral acid and optionally an organic acid having a pKa of 0 to 2, (), and / or releasing the monohydrochloride of the base of formula II and reacting, optionally without isolation, with 1-methylthio-1-methylamino-2-nitroethylene of formula III 17 18 CH3— s \ CCCH — NO OF CH 3 -NH (III) and optionally the hydrochloride of the base of formula I is isolated and purified and / or optionally liberated from the base of formula I and / or is optionally purified and converted into its hydrochloride. 2. A process according to claim 1, wherein the reaction of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride of formula IV with cysteamine hydrochloride uses p-toluenesulfonic acid as the catalyst. ' 3. The process of claim 1, wherein the reaction of 5-dimethylaminomethyl-2-furfuryl alcohol of formula IV with cysteamine hydrochloride is used as a thionyl chloride catalyst providing a catalytic amount of a mineral acid.