NO170543B - PROCEDURE FOR PREPARING THE HYDROCHLORIDE OF 1- (2- (5-DIMETHYLAMINOMETHYL-2- (FURYLMETHYLTHIO) -ETHYL)) - AMINO-1-METHYLAMINO-2-NITROETHYLENE - Google Patents

Description

The present invention relates to a process for producing the hydrochloride of 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methylamino-2-nitro-ethylene of formula (I):

and, if desired, to convert this compound into the base of formula (I).

Since the compound of formula (I) is a selective histamine H-2 receptor antagonist, it is an excellent drug against gastric and duodenal ulcers. For therapeutic purposes, the hydrochloride of the compound of formula (I) is used.

For the preparation of the hydrochloride of the compound of formula (I), the following processes are described in the literature.

a) According to example 32 in the published German patent application

2 7 34 070, the hydrochloride of the compound is prepared

of formula (I) by dissolving the base of formula (I)

in ethanol and precipitation of the hydrochloride formed by the addition of ethyl acetate, forming et

89.6% yield of the hydrochloride as calculated for the base used as starting material.

According to Belgian patent document 890 574 (page 2, line 5

to 7) the hydrochloride of the compound of formula (I) obtained in this way exhibits unsuitable filtering and drying properties, and this process does not have the desirable features of a production process.

b) According to example 1 in Belgian patent document 890 574, the hydrochloride is prepared from the compound of

formula (I) by adding concentrated aqueous hydrochloric acid to a solution of the base of formula (I) in aqueous isopropanol solution and precipitation of the hydrochloride formed by adding a further

amount of isopropanol, forming a 93.9% yield of the hydrochloride as calculated for the base.

The starting material for both processes is thus the basis of formula (I). Based on the currently known processes, the base of formula (I) must therefore first be prepared in a suitable quality for the formation of the hydrochloride.

Three processes for the synthesis of the base of formula (I) are described in published German patent application 2 734 070 (Examples 15, 20 and 21). Among these, the result indicated in Example 15 is most acceptable, according to which base of

formula (I) is prepared by reacting the base of formula (II)

with l-methylthio-l-methylamino-2-nitroethylene of formula (III):

for 8 hours in the presence of water. The base of formula (I) with a melting point of 69 to 70°C is obtained in a 78% yield as calculated for the compound of formula (II). A significant deficiency

by this description consists in that the exact conditions

for the recrystallization is not given, although these are of decisive importance both for the yield and the quality of the base of formula (I).

During investigations into this course of reaction, it was found that by following the process described in example 15, the base of formula (I) could not be obtained in a quality that enabled the production of a hydrochloride that meets the requirements for a technological process on an industrial scale and production of pharmaceutical preparations.

The difficulties associated with the preparation of the base of formula (I) and its hydrochloride suitable for pharmaceutical preparations, as well as the lack of a satisfactory solution to this problem, is also indicated by the fact that there are numerous further patent applications for the preparation of these compounds, as published British patent application 2 075 980 A, Belgian patent specification 886 997 and 890 574,

However, 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 55,625, 55,626, 59,082, and 64,869 provide processes that provide. is included in the patent documents and patent applications as stated above, no satisfactory solution to which. the difficulties associated with the industrial production of the hydrochloride of the base of formula (I).

The aim of the present invention is thus to provide a method for the preparation of the compound of formula (I) and its hydrochloride which enables the preparation of these compounds in good yield and in a simple manner on an industrial scale.

It has now unexpectedly been found that the above-mentioned disadvantages can be eliminated by reacting the monohydrochloride of the base of formula (II), instead of the base of formula (II) as starting material, with the compound of formula (III). In addition, it has been found that by using the monohydrochloride of the base of formula (II) as starting material, the hydrochloride of the compound of formula (I) usable for pharmaceutical preparations can be obtained directly.

This recognition could not be expected for several reasons. On the one hand, according to the published German patent application, is obtained

2,734,070 the base of formula (I) by reacting the base form of the compound of formula (II) with the compound of formula (III). On the other hand, it is well known that displacement of the methyl-thio group of amines, such as, for example, in the course of the reaction of the base of formula (II) with the compound of formula (III), is generally carried out with the amine bases and not with their hydrohalides [Houben -Weyl: Methoden der Organischen Chemie, Ed. E. Muller, Vol. IX, Georg Thieme Verlag, Stuttgart^ 1955, page 757, and in particular page 758; example 14a-j in published German patent application 2,734,070; example 1 in British patent specification 2 038 322] . Finally, on the basis of the methods known in the art, it would not be expected that the reaction of the monohydrochloride of the base of formula (II) with the compound of formula (III) would directly result in the formation of a preferred form of the hydrochloride of the compound of formula ( IN).

The compound of formula (III) used in the method according to the invention is known from the literature (published British patent application 2 075 960 A, page 3, example 1).

The monohydrochloride of the base of formula (II) used in the process according to the invention is a compound which, before its reaction with the compound of formula (III), can be prepared in good yield either separately or in situ from the hydrochloride of the base of formula (II), or , if desired, from the base of formula (II).

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

with cysteamine hydrochloride.

The invention thus relates to a method

for the preparation of the hydrochloride of 1-£2-[ji-dimethylamino-methyl-2-(furylmethylthio)-ethyljj -amino-1-methylamino-2-nitroethylene of formula (I), and, if desired, for the conversion of this compound to the base of formula (I), which method is characterized in that

the monohydrochloride of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran of formula (II):

1 is reacted with l-methylthio-l-methylanino-2-nitro-ethylene of formula "(III) :

optionally in the presence of water and/or an organic solvent,

and/or, if desired, that the base of formula (I) is released therefrom, and/or, if desired, that it is purified and converted to the hydrochloride thereof.

A preferred embodiment of the method

according to the invention comprises reacting the hydrochloride of the base of formula (II) prepared separately, with the compound of formula (III) at a temperature between 20 and 90°C. Alternatively, the monohydrochloride of the base of formula (II) can be formed in situ from the dihydrochloride of the base of formula (II) conveniently by neutralizing one molecule of hydrogen chloride present in the dihydrochloride with an alkaline agent, preferably using an alkali metal hydrogen carbonate, alkali metal carbonate or hydroxide or a suitable organic base, and that the monohydrochloride obtained in situ is reacted with the compound of formula (III). The method according to the invention can preferably be carried out in the presence of water and/or an organic solvent, e.g. methanol.

The free base of formula (II) can be released from its dihydrochloride obtained by the above-mentioned reaction either in situ or after separation of the dihydrochloride, by adding a suitable basic substance, e.g. an alkali metal hydroxide, to the dihydrochloride. From this base, the monohydrochloride can be formed in a known manner. Alternatively, however, the dihydrochloride salt of the base of formula (II) can be directly transferred to the monohydrochloride of the base of formula (II) without release of the base. From the monohydrochloride obtained in this way, the hydrochloride of 1-{2-[5-dimethylaminomethyl-2 -(furylmethylthio)-ethyljj -amino-1-methylamino-2-nitro-ethylene of formula (I) is directly prepared according to method n.

From the dihydrochloride of the base of formula (II) obtained in this way, the monohydrochloride of the base of formula (II) can be prepared and reacted with 1-methylthio-1-methylamino-2-nitroethylene of formula (III) as indicated above.

The reaction mixture, obtained as a result of the method according to the invention, mainly contains the hydrochloride of the base of formula (I), which crystallizes from the mixture, optionally after the addition of a suitable solvent or solvent mixture, e.g. aqueous ethanol or a mixture of ethanol with acetone to the reaction mixture.

The purity of the hydrochloride of the base of formula (I) obtained by the method according to the invention is at least 95%.

If desired, this product can be further purified using chromatography and/or fractional crystallization.

The hydrochloride of 5-dimethylaminomethyl-2-furfuryl alcohol of formula (IV) used in method b) according to the invention, is a known substance [J. Am. Chem. Soc. 69,

464 (1947)]. The cysteamine hydrochloride is commercially available.

The advantages of the method according to the invention can be summarized as follows.

When the direct aim is to prepare the hydrochloride of the base of formula (I), it is not imperative to prepare and separate the base of formula (I) in a separate step to form the hydrochloride. This is particularly advantageous as production of the base of formula (I) in a pure, crystalline form is problematic according to the state of the art.

By using the method according to the invention, the hydrochloride of the base of formula (I) is obtained directly in an advantageous crystalline form.

The volume requirement for the method according to the invention is very low, as no separate addition of any solvent to the reactants is necessary.

Based on these facts, the method according to the invention is applicable for simple preparation of the base of formula (I) and its hydrochloride in a good yield also on an industrial scale.

The dihydrochloride salt of the base of formula (II) is a well-defined, stable compound which can be stored without change, and from which, if desired, the base of formula (II) or the new monohydrochloride salt thereof can be prepared at any time, conveniently short before use.

The method according to the invention is further illustrated in the following examples.

A. Preparation of intermediate product.

Production 1

Preparation of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylamino-methylfuran-dihydrochloride [dihydrochloride of the base of formula (II)]

A mixture containing 9.08 g (0.08 mol) of cysteamine hydrochloride and 15.32 g (0.08 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride was fused together with stirring at 70 to 75°C, after which 0. 75 ml of concentrated hydrochloric acid was added and the mixture was further stirred at 80°C for 1 hour and at 90°C for 20 minutes under slightly reduced pressure

(40 to 60 kPa). After cooling to 70°C, 15 ml of absolute ethanol was added, and the reaction mixture was kept at room temperature for 2 hours, after which 15 ml of absolute acetone was added, and the mixture was kept at 0 to 4°C overnight, and the crystalline precipitate was filtered , washed

with a 1:1 mixture of ethanol and acetone and was dried to give 20.19 g (8 7.2%) of the desired product with srap. 160 to 162°C.

Manufacturing 2

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

A mixture containing 14.7 g (0.13 mol) of cysteamine hydrochloride, 23.0 g (0.12 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride and 5 ml of concentrated hydrochloric acid was heated to 60°C with stirring and within a few minutes. After approx. 10 minutes a melt was formed which was allowed to cool to room temperature, was stirred at room temperature for 6 hours and allowed to stand at room temperature for 60 hours. The crystalline mixture was suspended in 100 ml of ethanol, was dissolved by heating to the boiling point, was rapidly cooled with stirring and allowed to stand at 0 to 5°C for 1 hour, was filtered, washed with ice-cold ethanol and was dried to give 25 g (72.5%) of the desired product with m.p. 16 3 to 165°C after recrystallization from 96% ethanol.

Manufacturing 3

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

A mixture containing 19.0 g (0.167 mol) of cysteamine hydrochloride and 32.0 g (0.169 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride was fused at 67°C, after which 1.0 ml of concentrated hydrochloric acid was added . The temperature was raised to 90°C over 16 minutes, a further amount of 0.5 ml of concentrated hydrochloric acid was added, the mixture was stirred at this temperature for 40 minutes, was cooled to 80°C, after which 95 ml of absolute ethanol was added . The crystalline mixture was thoroughly stirred, cooled, filtered, washed with absolute ethanol and dried to give 40.1 g (83.7% as calculated for cysteamine hydrochloride) of the desired product, m.p. 159 to 161°C.

Manufacturing 4

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

A mixture containing 29.4 g (0.26 mol) of cysteamine hydrochloride and 45.96 g (0.24 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride was melted with stirring in a water bath maintained at 70 to 75°C . After an internal temperature of 60°C was reached (about 30 minutes), 3.6 ml of concentrated hydrochloric acid was added dropwise over 10 minutes, after which the mixture was stirred at 60°C for 3 hours and at 70°C for 1 hour. 60 ml of absolute ethanol was added, after which the mixture was allowed to cool to 40°C, 60 ml of acetone was added, the mixture was stirred for 2 hours at room temperature and was then kept at 5 to 10°C overnight. The precipitated crystals were collected,

washed with ethanol and acetone and dried in air to give 55.4 g (80.4%) of the desired product with m.p. 158 to 160°C.

Manufacturing 5

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

A mixture containing 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 was heated to 30°C with stirring to form of a homogeneous melt, after which 0.6 ml of concentrated hydrochloric acid and a solution of ethyl chlorosulphite (0.5 ml, prepared as described below) were added over 10 minutes, after which the mixture was stirred at 60°C for 3 hours and at 70°C for 1 hour. 20 mL of absolute ethanol was added, the mixture was allowed to cool to 40°C, 20 mL of acetone was added, the mixture was stirred at room temperature for 2 hours and then allowed to stand at 5 to 10°C overnight. Then, the method according to example 4 was followed to form 19.48 g (84.8%) of the desired product with m.p. 158 to 160°C.

The solution of ethyl chlorosulphite was prepared by dropping 2.8 ml of thionyl chloride into 10 ml of absolute ethanol kept at -20°C, after which the solution was stirred at -10°C for 30 minutes.

Manufacturing 6

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

A mixture containing 4.54 g (0.04 mol) of cysteamine hydrochloride and 7.66 g (0.04 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride was fused at 70 to 75 C with stirring, after which 0.18 ml of concentrated hydrochloric acid was added, the mixture was heated to 80°C, and 0.5 g of p-toluenesulfonic acid was added, after which the mixture was stirred at 80°C for 1 hour and at 90°C for 20 minutes under slightly reduced pressure (40 to 60 kPa). After cooling, the reaction mixture was worked up as described in example 1, forming 9.83 g (85.4%) of the desired product with m.p. 158-160°C.

Manufacturing 7

Preparation of 2-[(2-aminoethyl)-thiomethyl]-5-dimethyl-aminomethyl 1 furanic dihydrochloride

The procedure described in Example 6 was followed with the exception that 0.3 ml of 85% phosphoric acid was used instead of p-toluenesulfonic acid to form 9.8 g (85.3%) of the desired product with m.p. 158 to 160°C.

Manufacturing 8

Preparation of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylamino-methyl furan-dihydrochloride

A mixture containing 9.08 g (0.08 mol) of cysteamine hydrochloride and 15.32 g (0.08 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride was fused at 78°C,

0.2 ml of thionyl chloride was added and the mixture was 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 absolute ethanol was added, the mixture was heated to boiling, a further amount of 20 ml of absolute ethanol and 40 ml of acetone was added, and the mixture was allowed to stand at 5°C overnight. The precipitated crystals were washed with a 1:1 mixture of ethanol and acetone and

dried to give 19.6 g (85.3%) of the desired product with m.p. 156 to 158°C.

Production 9

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

The procedure described in example 8 was followed, with the exception that 1 g of aluminum chloride was used instead of thionyl chloride, producing 21.1 g (91.9%) of the desired product.

Production 10

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

An intimate mixture containing 95.75 g (0.5 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride, 64 g (0.52 mol) of 92% cysteanine hydrochloride and 9.3 ml of concentrated hydrochloric acid was stirred in the presence of 250 ml of benzene at 60 to 62°C for 4 hours. The benzene was decanted off and the residue was stirred with 235 ml of absolute ethanol on a water bath at 80°C for a few minutes after which 235 ml of acetone was added and the mixture was stirred and then kept at 0 to 4°C overnight. The crystalline precipitate was filtered, washed and dried to give 124.5 g (86.7%) of the desired product m.p. 161 to 164°C.

When 3.8 g of this product was recrystallized from 6 ml of ethanol and 6 ml of acetone was added with cooling, 3.59 g of an analytical sample with m.p. 163 to 166°C.

Production 11

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

The procedure described in example 10 was followed with the exception that instead of benzene, dichloroethane was used as diluent while stirring at the boiling point for 3.5 hours. The desired product was obtained in a yield of 89% with m.p. 157 to 161°C.

Production 12

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

The procedure described in example 10 was followed with the exception that petroleum ether (with a boiling point of 70 to 80°C) was used as diluent instead of benzene.

The desired product was obtained in a yield of 83% with m.p. 160 to 162°C.

Production 13

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

To a mixture containing 38.6 g (0.134 mol) of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran dihydrochloride and 19 ml of water was added 29 ml of 40% sodium hydroxide solution, and the base was extracted with 3 times 30 ml of ethyl acetate. The organic layers were combined, dried over anhydrous potassium carbonate, filtered, and the solvent was evaporated and the residue distilled under reduced pressure using a Vigreux column. The desired product was obtained in a yield of 22.88 g (79.4%), b.p. 116 to 120°C/13.3 Pa.

Production 14

Preparation of 2-[(2-aminoethyl)-thiomethyl]-5-dimethyl-aminomethylfuran monohydrochloride [monohydrochloride of the base of formula (II)]

To a suspension containing 2.87 g (0.01 mol) of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran dihydrochloride in 25 ml of absolute ethanol was added a solution of 1.0 g (0.01 mol ) potassium bicarbonate in 4 ml of water with stirring at 20°C. The mixture was stirred for 30 minutes,

the precipitated potassium chloride was filtered off, and the solution was evaporated to dryness. The residue was triturated with ether, filtered, washed with ether and dried to give 2.42 g (96%) of the desired product m.p. 115 to 116°C.

Production 15

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

A solution of 21.4 g (0.1 mol) of 2-[(2-aminoethyl)-thio-methyl]-5-dimethylaminomethylfuran base in 50 ml of methanol was added dropwise to a solution of 28.7 g (0 .1 mol) 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran dihydrochloride in 300 ml of methanol, after which the mixture was stirred for 10 minutes and then evaporated to dryness under reduced pressure. The residue was triturated with 100 ml of ether, kept at 0 to 4°C for 2 hours, filtered, washed with ether and dried at 20°C to give 48 g (89%) of the desired product with m.p. 111 to 112°C.

B. Manufacture of final product.

Example 1

Preparation of 1-{2-[(5-dimethylaminomethyl-2-(furylmethyl-thio)-ethyl)}-amino-1-methylamino-2-nitroethylene hydrochloride

[hydrochloride of the base of formula (I)]

A mixture containing 12.54 g (0.05 mol) of 2-[(2-amino-ethyl)-thiomethyl]-5-dimethylaminomethylfuran monohydrochloride, 7.41 g (0.05 mol) of 1-methylthio-1-methylamino -2-nitroethylene and 2.5 L of water were fused at 70 to 75°C with stirring for 2 hours. Gas evolution was observed. After cooling, the reaction mixture was dissolved in 70 ml of ethanol, first clarified with activated carbon, then with Hyflo<®>, the pH of the filtered solution was adjusted to 5 with concentrated aqueous hydrochloric acid, the solution was cooled to 0°C, inoculated and stirred at 0°C for a few hours and then allowed to stand at 0 to 4°C overnight. The precipitate was filtered, washed with absolute ethanol and dried at 50°C under reduced pressure to give 6.1 g (34.8%) of the desired product m.p. 139 to 141°C.

From the mother liquor a further amount of 3.8 g (21.7%) of the desired product of similar quality was obtained, m.p. 139 to 141°C.

Example 2

Preparation of 1-_2-[5-dimethylaminomethyl-2-(furylmethyl-thio)-ethyl])-amino-1-methylamino-2-nitroethylene hydrochloride

A solution of 1.0 g (0.01 mol) of potassium bicarbonate in 4 ml of water was added to 2.87 g (0.01 mol) of 2-[(2-amino-ethyl)-thiomethyl]-5-dimethylaminomethylfuran dihydrochloride . After stirring for 10 minutes, 1.52 g (0.0102 mol) of 1-methylthio-1-methylamino-2-nitroethylene was added, the mixture was stirred at 40 to 50°C for 1 hour, was heated to 60°C

during 10 minutes, stirred at 60°C for 1 hour and at 70°C

for 30 minutes. After cooling, 30 ml of absolute ethanol was added, the precipitated potassium chloride was filtered off, and the filtrate was evaporated to dryness under reduced pressure. The residue was dissolved in 13.8 ml of 96% ethanol, the pH value of the solution was adjusted to 5.5 to 6 by adding a few drops of aqueous, concentrated hydrochloric acid, the solution was stirred at 0°C for 3 hours and given stand at 0 to 4°C overnight. The precipitate was filtered and treated as described in Example 16, yielding 1.77 g (50.5%) of the desired product with m.p. 138 to 140°C.

From the mother liquor, a further amount of 0.19 g (5.4%) of the desired product was obtained, m.p. 138 to 140°C.

Example 3

Preparation of l-{2-[5-dimethylaminomethyl-2-(furylmethyl-thio)-ethyl]}-amino-l-methylamino-2-nitroethylene hydrochloride

A solution of 5.0 g (0.05 mol) potassium bicarbonate

1 20 ml of water was added to 14.35 g (0.05 mol) of 2-[(2-amino-ethyl)-thiomethyl]-5-dimethylaminomethylfuran dihydrochloride. After stirring for 10 minutes, 7.45 g (0.05 mol) of 1-methyl-thio-1-methylamino-2-nitroethylene was added, the mixture was stirred at 40 to 50°C for 1 hour, was heated to 60°C during 10 minutes, stirred at 60°C for 1 hour and at 70°C for 30 minutes. Then the reaction mixture was diluted with 30 ml of water, the pH of the solution was adjusted to 5 by adding 2 N aqueous hydrochloric acid, and the solution was extracted with 2 times 30 ml of chloroform. The pH of the aqueous layer was adjusted to 10 using 2 N aqueous potassium hydroxide solution, and the solution was extracted with 4 times 30 ml of chloroform. The combined organic phase was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in 70 ml of absolute ethanol and prepared first using activated carbon and then Hyflo®. Aqueous concentrated hydrochloric acid was added dropwise to the filtrate to adjust the pH to 5.5 to 6, after which the mixture was stirred (optionally after seeding) at 0°C for 3 hours and allowed to stand at 0 to 4°C overnight. The precipitate was filtered and treated as described in Example 16 to give 7.1 g (39%) of the desired product with m.p. 139 to 141°C.

From the mother liquor, a further amount of 3.5 g

(19%) of the desired product obtained, m.p. 139 to 141°C.

Example 4

Preparation of 1-{2-[5-dimethylaminomethyl-2-(furylmethyl-thio)-ethyljj--amino-1-methylamino-2-nitroethylene-hydrochloride

2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethyl-furan monohydrochloride produced in situ in an amount of

0.01 mol as described in Example 17 was mixed with 1.48 g (0.01 mol) of l-methylthio-l-methylamino-2-nitroethylene and was stirred at room temperature for 8 hours, was kept at room temperature for 14 hours and then stirred at the same temperature for 1 hour. 40 ml of water was added, the pH of the solution was adjusted to 5 by the addition of 2 N hydrochloric acid, the mixture was extracted with 3 times 10 ml of chloroform, the pH of the aqueous phase was adjusted to 10 by the addition of 2 N aqueous potassium -hydroxide solution, and the solution was extracted with 4 times 20 ml of chloroform. The combined organic phase was dried and evaporated under reduced pressure. The remaining impure base was dissolved in 4 volumes of absolute ethanol, clarified and filtered. The pH of the ethanolic solution was adjusted to 5 by the addition of aqueous concentrated hydrochloric acid at 0°C. The solution was seeded, stirred at 0°C for 3 hours and allowed to stand at 0 to 4 PC overnight. The precipitate was filtered, washed with ethanol and dried to give 1.05 g (29.9%) of the desired product m.p. 139 to 141°C.

From the mother liquor, 0.9 g (26%) of the desired product was isolated with m.p. 138 to 140°C.

From the impure base of formula (I) obtained during the work-up procedure, a crystalline product can be obtained in a known manner, e.g. by recrystallization from 4-methyl-2-pentanone, m.p. 6 7 to 68 C.

Claims (1)

Process for the preparation of the hydrochloride of 1-{2-[5-dimethylaminomethyl-2-(furyl-methylthio)-ethyl]}-amino-1-methylamino-2-nitroethylene of formula (I): and, if desired, for converting this compound into the base of formula (I), characterized in that the monohydrochloride of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran of formula (II): is reacted with l-methylthio-l-methylamino-2-nitro-ethylene of formula (III): optionally in the presence of water and/or an organic solvent, and, if desired, that the hydrochloride of the base of formula (I) is separated and purified, and/or, if desired, that the base of formula (I) is released therefrom, and/or, if desired, that it is purified and converted to the hydrochloride thereof .