KR910007966B1 - Process for preparing basic thioethers and the salts thereof - Google Patents

Abstract

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Description

Method for preparing basic thioether and salts thereof

The present invention provides a hydrochloride of 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) -ethyl]}-amino-1-methylamino-2-nitroethylene of the following general formula (I) To a base of formula (I) of this compound.

In addition, the present invention provides a novel main intermediate for the preparation of the compounds, namely dihydrochloride of 2-[(2-aminoethyl) -thiomethyl] -5-dimethylamino methylfuran of novel general formula (II) Monohydrochloride, and a method for preparing the same.

Compounds of formula (I), which are selective histamine H-2 receptor antagonists, are excellent agents for gastric and duodenal ulcers. For therapeutic purposes, hydrochlorides of general formula (I) compounds are used.

The following methods for preparing hydrochlorides of compounds of formula (I) are described in the literature.

a) According to Example 32 of German Patent Publication No. 2,734,070, the yield of 89.6% was obtained by dissolving the base of Formula (I) in ethanol and precipitating the hydrochloride produced by the addition of ethyl acetate. Hydrochloride of the compound of formula (I) is prepared. However, according to Belgian Kingdom Patent No. 890,574 (pages 2,5-7), the hydrochloride of the compound of general formula (I) obtained by the above method is inadequate as the preparation method because it shows inadequate filterability and dryness. I can't.

b) According to Example 1 of Belgian Kingdom Patent No. 890,574, 93.9% by adding a concentrated hydrochloric acid solution to a solution of the general formula (I) base dissolved in an isopropanol aqueous solution, and adding an additional amount of isopropanol to precipitate the resulting hydrochloride. A hydrochloride of the compound of formula (I) is prepared in the yield (calculated based on base).

The starting material used in these two methods is the base of formula (I). Therefore, on the basis of known methods in the present state, a base of general formula (I) of a suitable quality for preparing hydrochloride must be prepared.

Three methods for synthesizing the base of Formula (I) are described in Examples 15,20 and 21 of the above-mentioned German Patent Publication No. 2,734,070. Of these, the method of Example 15 is most suitable, and accordingly, the base of general formula (I) and 1-methylthio-1-methylamino-2-nitroethylene of general formula (III) are added for about 8 hours in the presence of water. By reacting, the base of general formula (I) is manufactured.

Thereby, the base of general formula (I) having a melting point of 69 to 70 ° C is obtained in 78% yield (calculated based on the general formula (II) compound). However, although the method implies decisive importance both in terms of yield and quality of the base of formula (I) obtained, it has a significant deficiency that does not describe the exact conditions necessary for recrystallization.

As a result of investigating the reaction process, the method described in Example 15 was prepared by formula (I) having a feature that enables the production of hydrochloride that satisfies the technical process on the industrial scale and the requirements for preparing the manufacturing composition. It was found that no base could be obtained.

In addition to the above problems which have not been satisfactorily solved, many patents exist for the preparation of these compounds (e.g. UK patents), since there are many difficulties associated with the preparation of the bases of formula (I) and their hydrochlorides useful for pharmaceutical preparations. Publication 2,075,980 A: Belgian Kingdom 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, and European Patent Publications 55,625, 55,626, 59,082 The fact that) is filed also reveals. However, the process described in this patent specification does not provide a satisfactory solution to the challenges associated with mass production of hydrochlorides of the base of formula (I).

It is therefore an object of the present invention to provide a process for the preparation of the general formula (I) compounds and their hydrochlorides by simple processes in good yields and on an industrial scale. It has surprisingly been found that the above-mentioned drawbacks can be eliminated by reacting with a compound of formula (III) by replacing the base of formula (II) with a monohydrochloride of the formula (II) base as starting material. It has also been found that hydrochlorides of compounds of formula (I) which are useful for pharmaceutical compositions can be obtained directly when using monohydrochlorides of the base of formula (II) as starting material.

The above findings were totally unpredictable for several reasons below; First, according to the German Patent Publication No. 2,734,070, a base of Formula (I) is obtained by reacting a base of Formula (II) with a Formula (III). Second, for example, it is known to replace a methylthio group with an amine using an amine base without using a hydrohalide of an amine base during the reaction of a base of formula (II) with a compound of formula (III) [ Houben-Weyl: Methoden der Organischen Chemie, ED. E. Muller, Vol. IX, Georg Thieme Verlag, Stuttgart, 1955, page 757 and especially page 758: Examples 14a-j of German Patent Publication No. 2,734,070: Example 1 of permanent patent No. 2,038,322]. Finally, the reaction of monohydrochloride of the general formula (II) base with the compound of the general formula (III) results in the direct preparation of the hydrochloride of the general formula (I) compound in the preferred form by the known methods. It cannot be predicted.

Compounds of formula (III) used in the process of the invention are already known in the literature (British Patent Publication No. 2,075,960A, page 3, Example 1).

Monohydrochloride novel compounds of the general formula (III) base for use in the process of the present invention, which are from, or if necessary, dihydrochloride of the new general formula (II) base prior to reacting with the general formula (III) compound. It may be prepared separately from the base of formula (II) or in insity in good yield. The present invention also relates to hydrochloride salts of the novel general formula (II) bases and their preparation.

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

Therefore, the present invention relates to a) monohydrochloride of 2-[(2-aminoethyl) -thiomethyl-5-dimethylamino metalfuran of formula (II) and 1-methylthio-1- of formula (III). Methylamino-2-nitroethylene in the presence of water and / or a solvent or b) hydrolysing cysteamine hydrochloride of 5-dimethylaminomethyl-2-furfuryl alcohol of formula (IV) to 20 Inorganic and optionally organic acids (pKa: 0-2) in the absence of a solvent at a temperature of from 120 ° C., in the presence of a catalytic amount of inorganic acid and optionally an organic acid (pKa value: 0 to 2), or under the above conditions, in the absence of a solvent, if necessary, are added thereto. After reaction in the presence of a catalytic amount of the material to give, if necessary, isolating the dihydrochloride of the prepared base of formula (II) and / or freeing the mono hydrochloride of the base of formula (II) therefrom, and then being React with 1-methylthio-1-methylamino-2-nitroethylene of formula (III) without separation, and if necessary the hydro of the base of formula (I) prepared by process a) or b) Isolating and purifying the chloride, and / or freeing the base of general formula (I) therefrom if necessary, and / or freeing the base of general formula (I) therefrom, if necessary, and / or purifying if necessary Of 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) -ethyl]} amino-1-methylamino-2-nitroethylene of formula (I) characterized by conversion to hydrochloride A novel process for preparing hydrochloride and, if necessary, a novel process for converting this compound to a base of formula (I).

A preferred embodiment of process a) of the present invention is to react the hydrochloride of formula (II) base prepared separately and the compound of formula (III) at a temperature of 20 to 90 ° C. Alternatively, a molecule of hydrogen chloride present in the dihydrochloride of the general formula (II) base may be neutralized by using an alkali agent, preferably by alkali metal carbonate, alkali metal carbonate or hydroxide, or by using an appropriate organic base. Monohydrochloride of the general formula (II) base is obtained by itself from the dihydrochloride of the general formula (II), and the obtained monohydrochloride is reacted with the general formula (III) compound.

Process a) of the present invention may preferably be carried out in the presence of water and / or an organic solvent (eg methanol). Preferred embodiments of process b) of the present invention do not add the hydrochloride and cysteamine hydrochloride of the general formula (IV) compound in the presence of a catalytic amount of inorganic acid (preferably hydrochloric acid), and if necessary in the presence of an inert organic diluent Under an optional vacuum. This reaction is carried out at a temperature of 20 to 120 ° C, preferably 20 to 75 ° C. A portion of the catalytic amount of inorganic acid can be similarly replaced by an organic acid of strength (pJa value: 0-2), preferably sulfonic acid (eg paratoluenesulfonic acid).

Dihydrochloride salts prepared according to the process of the invention can be separated by known methods. For example, the dihydrochlorides of the general formula (II) base are mostly in crystalline form by adding lower alkanols (e.g. ethanol) or mixtures of lower alkanols and lower aliphatic ketones (e. G. Acetone) to the cooled reaction mixture. It is precipitated and can be separated by filtration.

In the process dihydrochloride of the formula (II) base can be obtained, for example in a yield of 87%.

The free base of formula (II) is freed on its own from the dihydrochloride obtained in the above-mentioned reaction or by separating the dihydrochloride by adding a suitable basic substance (e.g. alkali metal hydroxide) to the dihydrochloride chloride. Can be maintained. From this base monohydrochloride can be prepared by techniques known in the art. However, the dihydrochloride salt of the general formula (II) base obtained by the process of the present invention can be converted directly to the monohydrochloride of the general formula (II) base without liberating the base. From monohydrochloride obtained by this method, 1- [2- [5-dimethylaminomethyl-2- (furylmethylthio) -ethyl]}-amino-1-ethylamino-2-nitro of formula (I) Hydrochlorides of ethylene can be prepared directly by process a).

Another preferred embodiment of the process b) of the present invention is a substance which provides, under reaction conditions, an inorganic acid or an inorganic acid and an organic acid of similar strength as the inorganic acid, preferably a phosphorus halide (eg phosphorus oxychloride) or an organic or inorganic acid halide (Eg, thionyl chloride, paratoluenesulfonyl chloride) or a catalytic amount of aluminum chloride is added to a mixture containing the hydrochloride and cysteamine hydrochloride of the general formula (IV) compound, and these are solvent at a temperature of 50 to 90 ° C. It is reacted for 2 to 3 hours in absence. In this process dihydrochloride of the general formula (II) base can be obtained in 82-92% yield.

According to the process b) of the present invention, the hydrochloride salt of the compound of formula (IV) can be melted with cysteamine hydrochloride in the presence of an inert organic limestone which is not dissolved in any starting hydrochloride if necessary. It may be particularly advantageous to use diluents when the process of the invention is used in mass production. As the diluent, aliphatic, aromatic or halogenated aliphatic hydrocarbons may be appropriately used. It is preferable to use benzene, toluene, dichloroethane or petroleum ether (boiling point (60-100 degreeC)) as a diluent in the said melting reaction.

Monohydrochloride of the general formula (II) was prepared from dihydrochloride of the general formula (II) base obtained by the above method, and this procedure described above was 1-methylthio-1-methyl of the general formula (III). React with amino-2-nitroethylene.

The reaction mixture obtained by the process of the present invention essentially contains a hydrochloride of the general formula (I) base, which adds a suitable solvent or mixture of solvents (e.g. aqueous ethanol or a mixture of ethanol and acetone) to the reaction mixture. After optional addition, crystallization precipitates from the mixture.

The purity of the hydrochloride of the general formula (I) base obtained in the present invention is at least 95%. If necessary, further purification can be performed using chromatography and / or fractional crystallization.

The hydrochloride of 5-dimethylaminomethyl-2-furfuryl alcohol of general formula (IV) used in process b) of the invention is a known substance [J. Am. Chem. Soc. 69464 (1947).

Cysteamine hydrochloride is one commonly used.

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

When the original purpose is to produce a hydrochloride of the general formula (I) base, it is not necessary to prepare and separate the base of the general formula (I) in a separate process to prepare the hydrochloride. The known technique is particularly advantageous in this respect, since it is problematic to prepare the base of formula (I) in pure crystalline form.

Using the process of the invention, the hydrochloride of the general formula (I) base is obtained directly in the advantageous crystalline form.

In the process of the present invention, the required volume required is very low because no solvent is added to the reactants.

Based on this fact, the process of the present invention is useful for the simple preparation of the base of formula (I) and its hydrochloride in good yield on an industrial scale.

The dihydrochloride salts of the novel general formula (II) bases prepared by the process of the invention are not deteriorated on storage because they are clearly defined stable compounds, from which if necessary the bases of general formula (II) or novel Its monohydrochloride salt can be prepared simply at any time before use.

The method of the present invention is described in detail by the following examples, which do not limit the invention.

Example 1

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

The mixture containing cysteamine hydrochloride (9,08 g, 0.08 mole) and 5-dimethylamino methyl-2-furfuryl alcohol hydrochloride (15.32 g, 0.08 mole) was melted at 70-75 ° C. with stirring After adding concentrated hydrochloric acid (0.75 ml), the mixture was stirred at 80 ° C. for 1 hour while gradually reducing the pressure (4 to 60 KPa), and further stirred at 90 ° C. for 20 minutes. After cooling to 70 ° C., anhydrous ethanol (15 ml) was added and the reaction mixture was left at room temperature for 2 hours, anhydrous acetone (15 ml) was added, the mixture was left at 0-4 ° C. overnight, and the crystalline precipitate was filtered off. The mixture was washed with a 1: 1 mixture of ethanol and acetone and dried to obtain 20,19 g (87.2%) of the desired product having a melting point of 160 to 162 캜.

Example 2

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

A mixture of cysteamine hydrochloride (14.7 g, 0.13 mole) 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (23.0 g, 0.12 mole) and hydrochloric acid (5 ml) is heated to 60 ° C. within minutes with stirring. . After about 10 minutes, the melt is cooled to room temperature, stirred for 6 hours at room temperature and left at room temperature for 60 hours. The crystalline mixture was suspended in ethanol (100 ml), heated to a boiling point, dissolved, quenched with stirring, left at 0-5 ° C. for 1 hour, filtered, washed with ice-cold ethanol, dried and recrystallized from 96% ethanol. The melting point is then 163 to 165 ° C. to obtain 25 g (72.5%) of the desired product.

Example 3

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

Cysteamine hydrochloride (19.0 g, 0.167 moles) After a mixture of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (32.0 g, 0.169 moles) is melted, hydrochloric acid (5 ml) is added. The temperature is raised to 90 ° C. within 16 minutes, and further concentrated hydrochloric acid (1.0 ml) is added, then the mixture is stirred at this temperature for 40 minutes, cooled to 80 ° C. and anhydrous ethanol (95 ml) is added. The crystalline mixture is thoroughly stirred, cooled, filtered and washed with anhydrous ethanol and dried to yield 40.1 g (83.7%, calculated on the basis of cysteamine hydrochloride) having a melting point of 159-161 ° C.

Example 4

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

A mixture of cysteamine hydrochloride (29.4 g, 0.24 mole) and 5-dimethylaminomethyl-2-furfuryl alcohol dihydrochloride (45.96 g, 0.24 mole) is melted with stirring in a water bath at 70 to 75 ° C.

After the internal temperature reached 60 ° C. (about 30 minutes), concentrated hydrochloric acid (3.6 ml) was added dropwise within 10 minutes, and then the mixture was stirred at 60 ° C. for 3 hours and at 70 ° C. for 1 hour. After adding anhydrous ethanol (60 ml), the mixture was cooled to 40 ° C., followed by the addition of acetone (60 ml), stirred at room temperature for 2 hours and then left at 5 to 10 overnight. The precipitated crystals are collected, washed with ethanol and acetone and dried in air to give 55.4 g (80.4%) of the desired product with a melting point of 158-160 ° C.

Example 5

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

A mixture of cysteamine hydrochloride (9.08 g, 0.08 mole) and 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (15.32 g, 0.08 mole) and water (1 ml) was heated to 30 ° C. with stirring and uniform After obtaining the melt, concentrated hydrochloric acid (0.6 ml) and ethyl chlorosulfite solution (0.5 ml, prepared by the following method) are added within 10 minutes, and the mixture is stirred at 60 ° C. for 3 hours at 70 ° C. for 1 hour. After adding anhydrous ethanol (20 ml), the mixture is cooled to 40 ° C., acetone (20 ml) is added, stirred at room temperature for 2 hours and left at 5-10 ° C. overnight. Next, according to the method described in Example 4, 19.48 g (84.8%) of the desired product having a melting point of 158 to 160 ° C is obtained.

The ethylchlorosulfite solution is prepared by dropwise addition of thionyl chloride (2.8 ml) to anhydrous ethanol (10 ml) maintained at -20 ° C, followed by stirring the solution at -10 ° C for 30 minutes.

Example 6

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

A mixture of cysteamine hydrochloride (4.54 g, 0.04 mole) and 5-dimethylamino methyl-2-furfuryl alcohol hydrochloride (7.66 g, 0.04 mole) is melted at 70-75 ° C. with stirring and concentrated hydrochloric acid (0.18 ml) is added, then heated to 80 ° C., and P-toluenesulfonic acid (0.5 g) is added, followed by stirring for 1 hour at 80 ° C. and 20 minutes at 90 ° C. under reduced pressure (40 to 60 KPa). After cooling, the reaction mixture is treated as described in Example 1 to yield 9.83 g (85.4%) of the desired product having a melting point of 158 to 160 ° C.

Example 7

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

Except for using 85% phosphoric acid (0.3 ml) in place of the P-toluenesulfonic acid of Example 6, 9.8 g (85.3%) of the desired product having a melting point of 158 to 160 ° C. was obtained by the method described in Example 6.

Example 8

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

A mixture of cysteamine hydrochloride (9.08 g, 0.08 mole) and 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (15.32 g, 0.08 mole) is melted at 75 ° C. and thionyl chloride (0.2 ml) After stirring for 10 minutes at 80 ° C., the mixture was further stirred at 80 ° C. for 50 minutes and at 90 ° C. for 20 minutes while slowly depressurizing. After cooling to 70 ° C., anhydrous ethanol (20 ml) is added and heated to boil, further anhydrous ethanol (20 ml) and acetone (40 ml) are added and left at 5 ° C. overnight.

The crystalline precipitate is washed with a 1: 1 mixture of ethanol and acetone and dried to give 19.6 g (85.3%) of the desired product having a melting point of 156 to 158 ° C.

Example 9

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

21.1 g (91,9%) of the desired product were obtained in the same manner as in Example 8, except that aluminum chloride (1 g) was used instead of thionyl chloride of Example 8.

Example 10

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

A mixture of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride (95.75 g, 0.5 mole), 92% cysteamine hydrochloride (64 g, 0.52 mole) and concentrated hydrochloric acid (9.3 mL) in benzene (250 ml) Stir at 60-62 ° C. for 4 hours. The benzene was decanted off and the residue was stirred with anhydrous ethanol (250 ml) in a water bath at 80 ° C. for several minutes and then left at 0-4 ° C. overnight. The crystalline precipitate is filtered, washed and dried to give 124.5 g (86.7%) of the desired product having a melting point of 163 to 164 ° C.

3.8 g of the present product is recrystallized from ethanol (6 ml), and 3.59 g of analytical sample having a melting point of 163 to 166 ° C. to which cooled acetone is added is obtained.

Example 11

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

The method described in Example 10 is carried out except that dichloroethanol is used as the diluent with stirring at the boiling point of 3.5 hours instead of the benzene of Example 10.

A desired product having a melting point of 157 to 161 ° C. is obtained in a yield of 89%.

Example 12

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

The same method as in Example 10 is used except that petroleum ether (boiling point 70 to 80 ° C.) is used instead of benzene as the diluent. The yield of the desired product is 83% and the melting point is 160 to 162 캜.

Example 13

Preparation of 2-[(2-aminoethyl) -thiomethyl] -5-dimethylamino ethylfuran base from dihydrochloride [Base of Formula (II)]

To a mixture containing 2-[(2-aminoethyl) -thiomethyl] -5-dimethylamino methylfuran dihydrochloride (38.6 g, 0.134 mol) and water (19 ml) was added 40% sodium hydroxide solution (29 ml). The base is then extracted with ethyl acetate (30mlX3).

The organic layer was collected, dried over anhydrous potassium carbonate, filtered, the solvent was evaporated and the residue was distilled coercively using a Vigreux fractionator. The yield of the desired product is 22.88 g (79.4%) and the boiling point is 116 to 120 ° C / 13.3 Pa.

Example 14

Preparation of 2-[(2-aminoethyl) -thiomethyl] -5-dimethylamino methylfuran monohydrochloride [monohydrochloride of a base of formula (II)].

In a suspension containing anhydrous ethanol (25 ml) and 2-[(2-aminoethyl) -thiomethyl] -5-dimethylamino methylfuran dihydrochloride (2.87 g, 0.01 mol), water (4 ml) and potassium hydrogen carbonate ( 1.0 g, 0.01 mol) is added at 20 ° C. and under stirring. After the mixture is stirred for 30 minutes, the precipitated potassium chloride is filtered and the solution is evaporated to dryness. The residue is triturated with ether, filtered and then washed with ether and finally dried to give 2.42 g (96%) of the desired product having a melting point of 115 ° C to 116 ° C.

Example 15

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

A solution of 2-[(2-aminoethyl) -thiomethyl] -5-dimethylamino methylfuran base (21.4 g, 0.1 mol) and methanol (50 ml) was added to 2-((2-aminoethyl) -thiomethyl] After dropwise addition to a solution consisting of -5-dimethylamino methylfuran dihydrochloride (18.7 G, 0.1 mol) and ethanol (300 ml), the mixture was stirred for 10 minutes and then evaporated to dryness under reduced pressure. 100 ml), left for 2 hours at 0 ° C. to 4 ° C., then filtered, washed with water and dried at 20 ° C. to obtain 48 g (89%) of the desired product having a melting point of 111 to 112 ° C.

Example 16

1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) -ethyl]}-amino-1-methyl-amino-2-nitroethylene hydrochloride [hydrochloride of the base of formula (I)] Produce

2-[(2-aminoethyl) -thiomethyl] -5-dimethylamino methylfuran monohydrochloride (12.54 g, 0.05 mole), 1-methylthio-1-methylamino-2-nitroethylene (7.41 g, 0.05 The mixture containing molar) and water (2.5 (ml) are melted under stirring for 2 hours at 70 ° C. to 75 ° C. At this time, gas is generated. After cooling, the reaction mixture is dissolved in ethanol (70 ml) and then activated first. Charcoal is then purified by Hyflo and then the pH value of the filtrate is adjusted to 5 with concentrated aqueous hydrochloric acid solution, then inoculated and stirred at 0 ° C. for several hours and left at 0-4 ° C. overnight. The precipitate is filtered off, washed with anhydrous ethanol and then dried at 50 ° C. and reduced pressure to give 6.1 g 934.8% of the desired product having a melting point of 139 to 141 ° C.).

An additional 3.8 g (21.7%) of almost the same desired product (melting point 139-141 ° C.) is obtained from the mother liquor.

Example 17

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

A solution consisting of potassium hydrogen carbonate (1.0 g, 0.01 mol) and water (4 ml) was added to 2-[(2-aminoethyl)

-Thiomethyl] -5-dimethylamino methylfuran dihydrochloride (2.87 g, 0.01 mol). After stirring for 10 minutes, 1-methylthio-1-methylamino-2-nitroethylene (1.52 g, 0.0102 mol) is added, and then the mixture is stirred at 40 to 50 ° C. for 1 hour, and then 10 minutes Heat 60 ° C inside, stir at 60 ° C for 1 h and then stir again at 70 ° C for 30 min. After cooling, anhydrous ethanol (30 ml) is added, the precipitated potassium chloride is filtered off and the filtrate is evaporated to dryness under reduced pressure. The residue was dissolved in 96% ethanol (13.8 ml) and the pH of the solution was adjusted to 5.5-6 by addition of concentrated aqueous hydrochloric acid solution and drops, then stirred at 0 ° C. for 3 hours and then left at 0-4 ° C. overnight. do. The precipitate is filtered and treated as in Example 16 to yield 1.77 g (50.5%) of the desired product with a melting point of 138-140 ° C.

Further obtained from the mother liquor is 0.19 g (5.4%) of the desired product having a melting point of from 138 to 140 ° C.

Example 18

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

A solution of potassium hydrogen carbonate (5.0 g, 0.05 mole) dissolved in water (20 ml) was added to 2-[(2-aminoethyl) -thiomethyl] -5-dimethylaminomethylfuran dihydrochloride (14.35 g, 0.05 mole). do. After stirring for 10 minutes, 1-methylthio-1-methyl amino-2-nitroethylene (7.4 g, 0.05 mole) was added, stirred at 40-50 ° C. for 1 hour, and then heated to 60 ° C. within 10 minutes, Stir at 60 ° C. for 1 hour and at 70 ° C. for 30 minutes. Then, half the mixture was diluted with water (30 ml), 2N hydrochloric acid aqueous solution was added to adjust the pH value of the solution to 5, followed by extraction with chloroform (30 ml × 2). The pH value of the aqueous layer was adjusted to 10 using 2N aqueous potassium hydroxide solution and then extracted with chloroform (30ml × 4). The collected organic layer is dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in anhydrous ethanol (70 ml) and then purified using first activated charcoal and then hyflo. To the filtrate is added dropwise aqueous hydrochloric acid solution to adjust the pH value to 5.5. ~ 6, then the mixture is stirred at 0 ° C. for 3 hours (after random inoculation) and left at 0-4 ° C. overnight. The precipitate was filtered and then treated as in Example 16 to yield 7.1 g (39%) of the title compound having a melting point of 139-141 ° C.

From the mother liquor an additional 3.5 g (19%) of the desired product having a melting point of 139-141 ° C. is obtained.

Example 19

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

2-[(2-aminoethyl) -thiomethyl] -5-dimethylamino methylfuran monohydrochloride prepared by itself in an amount of 0.01 mol in Example 17 was substituted with 1-methylthio-1-methylamino-2-nitro. It is mixed with ethylene (1.48 g, 0.01 mol) and then stirred at room temperature for 8 hours, left at room temperature for 14 hours and then at the same temperature for 1 hour.

The pH value of the solution was adjusted to 5 by adding water (40 ml), followed by 2N hydrochloric acid, the mixture was extracted with chloroform (10 ml × 3), and then the pH value of the aqueous layer was adjusted to 10 by adding 2N aqueous potassium hydroxide solution, followed by chloroform. Extract with (20ml × 4). The collected organic layer is dried and then evaporated under reduced pressure. The remaining crude base is dissolved in anhydrous ethanol (4 volumes), then purified and filtered. The pH value of the ethanolic solution is adjusted to 5 by adding concentrated hydrochloric acid aqueous solution at 0 degreeC. The solution is inoculated and then stirred at 0 ° C. for 3 hours and left at 0-4 ° C. overnight. The precipitate is filtered off, washed with ethanol and dried to yield 1.05 g (29.9%) of the desired product having a melting point of from 139 to 141 ° C.

0.9 g (26%) of the desired product having a melting point of 138-140 ° C. is separated from the mother liquor.

The crude base of general formula (I) obtained during the process operation is recrystallized by a known method, for example 4-methyl-2-pentanone having a melting point of 67 to 68 ° C., to obtain a crystalline product.

Claims (2)

Monohydrochloride of 2-[(2-iminoethyl) -thiomethyl] -5-dimethylamino methylfuran of the following general formula (II) and 1-metall-l-methylamino of the following general formula (III) The 2-nitromethylene can be reacted in the presence or absence of water, an organic solvent, or a mixed solvent thereof, and the hydrochloride of the general formula (I) obtained can be separated and purified, from which the base of the general formula (I) 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) of formula (I), characterized in that it can be liberated, which can be further purified and converted back to its hydrochloride. -Ethyl]}-amino-1-methylamino-2-methylamino-2-nitroethylene hydrochloride and process for preparing the base thereof.

The process according to claim 1, wherein the monohydrochloride of the base of formula (II) and 1-methylthio-1-methylamino-2-nitroethylene of formula (III) are reacted at a temperature of 20 to 90 ° C.