NO168942B - PROCEDURE FOR THE PREPARATION OF 2 - ((2-AMINOETHYL) -THIOMETHYL) -5-DIMETHYLAMINOMETHYLFURAN AND ACID ADDITION SALTS THEREOF - Google Patents

Description

The present invention relates to a method

for the production of 2-f(2-aminoethyl)-thiomethyl]-5-dimethyl-aminomethylfuran with formula (-1)

and acid addition salts thereof.

The compound of formula (I.) and its acid addition ions

salts are intermediates for the preparation of l-$2-[-5-di-methylaminomethyl-2-(furylmethylthio)-ethyl])-amino-l-methyl-amino-2-nitroethylene with formula (II)

which is a known excellent remedy for gastric and duodenal ulcers (Brit. J. Pharmacol. 72, 49, 55 (1981)).

For the production of the base with formula (I), two methods are described in the published DE patent application no. 2 734 070. Below, these methods will be referred to as "known method A" and "known method B", respectively.

According to the known method A which is indicated in example A (page 37) in the above-mentioned patent application,

is kept a mixture containing cysteamine hydrochloride, 5-dimethylaminomethyl-2-furfuryl alcohol of formula (IV)

and concentrated hydrochloric acid, at 0°C for 18 hours. In this reaction, the hydrochloric acid is present in an approx. 10 times molar excess. After processing and distillation, the base form with formula (I) is obtained in a yield of approx. 54%.

Using our own experiments, it was demonstrated that this moderate yield is a consequence of the extremely acidic medium, under these conditions the reaction is accompanied by a strong tar formation.

It should be noted that the sensitivity of furan derivatives to acids is well known from the literature (see, e.g., Rodd's Chemistry of Carbon Compounds, Ed. S. Coffey, Vol. IV/A, page 91, Elsevier Co., New York, 1973) .

The disadvantages of this method are set out below.

The duration of the reaction necessary to prepare the compound of formula (I) is too long.

The reaction medium is highly corrosive.

The base of formula (I) obtained after distillation is unstable even when stored in a refrigerator at a temperature between 0 and 4°C; after a few days it turns dark. After that, it is not uniform, i.e. it becomes unsuitable for further use within a relatively short time. The instability, especially to heat, of the free base of formula (I) is clearly demonstrated by the fact that at least 60 to 70% can be recovered without decomposition even when the uniform, pure base is subjected to distillation under greatly reduced pressure and at relatively low temperature, e.g. at 120 to 124°C and a pressure of 80 to 107 Pa.

For the reasons mentioned above, it can be concluded that

that the known method A is not suitable for large-scale production.

The known method B is only partially indicated in example D (page 40), example E (page 41) and example 1

(page 48) in the above-mentioned patent application. According to these examples, the base of formula (I) is prepared in three steps. In the first step (example D on page 40), 2-furylmethylmercaptan is condensed with N-(2-bromomethyl)-phthalimide so that 2-(2-phthalimidethyl)-thiomethylfuran is obtained in a yield of 52.3%,

in the second step (example E on page 41) this is postponed

product for a Mannich reaction with dimethylamine hydrochloride and formaldehyde so that 2-[(2-phthalimidethyl)-thio-methyl]-5-dimethylaminomethyl.f uran is obtained, i.e. the phaloyl derivative of the compound of formula (I) in a yield of 47.3%, finally this latter compound is dephthaloylated in the third step (Example 1 on page 48) whereby the salt of the base of formula (I) with phthalic acid hydrazide is obtained. The separation of the compound of formula (I) and the yield are not indicated, the known process B cannot therefore be used for comparison. In our own experiments, it has been found that the yield in the third step, i.e. in the dephthaloylation, cannot be considered more than 84%. Consequently, the total yield of the known process B, calculated on the basis of 2-furylmethylmercaptan as starting material used in the first step, is a maximum of 20.78% for the base of formula (I).

For a complete comparison between the known processes A and B, it is useful to trace back both the starting material of the known process A, i.e. the compound of formula (IV), and the starting material of the known process B, i.e. 2-furylmethylmercaptan, to 2 -furfuryl alcohol, i.e. to the common, commercially available base compound for both starting compounds. The yield known from the literature for the compound of formula (IV)

is 70% calculated for 2-furfuryl alcohol (J. Chem. Soc. 1958, 4728), while the yield known from the literature for 2-furylmethylmercaptan is 60% calculated for 2-furfuryl alcohol (Organic Syntheses Coll. Vol. 4_, page 4 91, John Wiley and Sons, Inc., New York, 1963).

Of the two methods known from the literature, it is obvious that the method A known therein is clearly preferable as the base of formula (I) is obtained in this way from the common, commercially available base compound in fewer steps and in a higher overall yield ( i.e. 37.8%) compared to the total yield (i.e. 12.4 7%) of the known method B. However, as indicated above, the known method B also has a number of disadvantages, mainly in terms of large-scale production.

The purpose of the present invention is thus to provide a new method for the preparation of the known compound of formula (I) and/or of the acid addition salts thereof, which does not have the disadvantages of the above-mentioned methods which are known from the past, and to make it possible to prepare the compounds of formula (I) and/or the acid addition ion salts thereof in a good yield and in a simple manner also on an industrial scale.

Now it has been unexpectedly found that the compound with formula

(I) can be prepared in a much more advantageous way than via the methods indicated above, by reacting cysteamine or an acid addition salt thereof with the new zwitterion (5-dimethyl-aminomethyl-2-furylmethyl) hydrogen sulfate of formula (III), which again can be obtained from 5-dimethylaminomethyl-2-furfuryl alcohol of formula (IV) in excellent yield. Furthermore, it has been found that the base of formula (I) which can be used directly for the preparation of the compound of formula (II), or any desired acid addition salt of the base of formula (I), can be easily obtained in a pure form from the new salts thereof prepared in this way. The present invention thus relates to a method for the production of 2-[(2-aminoethyl)-thiomethyl)-5-dimethylaminomethylfuran with formula (i) and acid addition salts thereof. The procedure is characterized by the fact that the zwitterion (5-dimethylaminomethyl-2-furylmethyl)- hydrogen sulfate of formula (III) is reacted with cysteamine or with an acid addition salt thereof, after which, if desired, an obtained acid addition salt of the base of formula (I) is separated, and/or, if desired, the base of formula (I) is liberated, purified and/or converted into another acid addition salt of the base of formula (I). The starting compound with formula (III) can be prepared by 5-dimethylaminomethyl-2-furfuryl alcohol med formula (IV)

is reacted with sulfur trioxide or with an agent suitable for introducing sulfur trioxide in the presence of a solvent, after which the obtained (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulfate of formula (III) is separated.

A preferred embodiment of the method according to the invention comprises melting the zwitterion of formula (III) with an acid addition salt (e.g. with the hydrochloride) of cysteamine under nitrogen or under vacuum at a temperature between 60 and 90°C without adding any solvent .

The production of the starting compound of formula (III) may comprise reacting 5-dimethylaminomethyl-2^furfuryl alcohol of formula (IV) with a complex formed from dimethylformamide and sulfur trioxide and used in an approximately 1:1 molar ratio in dimethylformamide as solvent . During the reaction, the zwitterionic compound of formula (III) is precipitated from the mixture as a solid and it can be easily separated after completion of the reaction. The separated zwitterionic compound can preferably be reacted with cysteamine or with an acid addition salt thereof.

In the preparation of the starting compound, the zwitter-ion compound of formula (III) can also be formed in acetonitrile or carbon tetrachloride instead of in dimethylformamide.

After alkalinization of an aqueous solution of the melt, which is composed of a mixed monohydrochloride-monohydrogen-sulphate salt of the base of formula (I), the base of formula (I) can be extracted into an organic solvent. The raw

base of formula (I) obtained _as the evaporation residue from the organic extract, or the pure base of formula (I) obtained from the extract by distillation, may be converted into any desired acid addition salt of the base of formula (I) after addition of the appropriate acid component. The salt of the base of formula (I) which is formed by the process

however, the method according to the invention can also

is converted directly without liberating the base, into another acid addition ion salt of the base with formula (I).

As an example of the conversion of an acid addition salt of the base of formula (I) obtained by the process according to the invention into another acid addition salt thereof, the hydrochloride can be preferably prepared by first separating the base of formula (I) in the recovery method mentioned above and then by to acidify a solution thereof in a lower aliphatic alcohol, e.g. in ethanol, with a solution of dry hydrogen chloride gas in the appropriate lower alkanol. Thus, the dihydrochloride of the base of formula (I) is obtained as a crystalline precipitate.

A monohydrochloride can also be formed from the base of formula (I) in a known manner.

Cysteamine and its salts used in the method according to the invention are known compounds,

some of which are commercially available.

Instead of the complex formed by sulfur trioxide and dimethylformamide, the complex of sulfur trioxide with pyridine and dioxane, respectively, can also be used in the preparation of the starting compound. All these complexes are known from the literature (see, for example, J. Am. Chem. Soc. 81, 1764 (1959); Chem. and Ind. 1966, 900).

5-Dimethylaminomethyl-2-furfuryl alcohol with formula

(IV) which is used in the preparation of the starting compound.

is also a compound known from the literature (J. Am. Chem. Soc. 6J3, 464 (1947).

The advantages of the method according to the invention are summarized below.

In contrast to the known method A, required

there are no large quantities of a concentrated mineral acid for the reaction, the risk of corrosion is consequently considerably less.

It is mainly due to the elimination of the strong acid that the reaction temperature in the method according to the invention can be increased significantly (e.g. from 0°C to 90°C) without any deterioration in the quality of the product, whereby the reaction time is also reduced considerably. All these factors contribute to the formation of a tar-free product of good quality.

The salts of the base of formula (I) prepared according to the process according to the invention are well-defined, stable substances from which, if desired, the base of formula (I) can be released at any time and at a suitably short time before use.

Some of the acid addition salts of the base with formula (I) prepared according to the process according to the invention can be used directly (ie without liberating the base) for the preparation of 1-^2-[(5-dimethylaminomethyl-2-(furylmethylthio)-ethyl] J-amino-l-methylamino42-nitroethylene of formula (II).

The volume needed for the reaction is significantly reduced by eliminating the excess of acid, i.e. by carrying out the reaction through melting, thereby increasing the efficiency of the utilization of the equipment capacity.

When 5-dimethylaminomethyl-2-furfuryl alcohol of formula (IV) is prepared according to the literature (J. Am. Chem. Soc. 69, 464 (1947), the distilled base of formula (IV) contains a large amount (in some cases 10 to 29%) of pollutants. When the compound of formula (IV,) thus obtained is converted directly to the base of formula (I) according to the method described in example a) (page 37) of published DE patent application no. 2 734,070, a significant amount of impurities, mainly tars, is formed due to the large excess of acid during the reaction, even when the reaction temperature is low. In contrast, when a product of formula (IV) is converted into the new zwitterionic compound of formula (III) according to the process described herein, the impurities arising during the preparation of the compound of formula (IV) and affecting the

unfavorable way the turnover of the compound of formula (IV)

with cysteamine hydrochloride, in the mother liquor remaining after filtering out the zwitterionic substance, consequently the reaction with cysteamine or with an acid addition salt thereof, which is carried out in the subsequent step, is not disturbed.

According to the known method A, the yield of the distilled base of formula (I) calculated for the compound of formula (IV) is approx. 54%. Since the zwitterionic compound of formula (III) is obtained from the compound of formula (IV) in a 92.8% yield and since the compound of formula (III) can be converted to the base of formula (I) in a yield of 68.9% according to method according to the invention, the total yield of the distilled base of formula (I) is calculated for the compound of formula (IV). 63.9%, i.e. much better than the yield of the known method A.

It is obvious that the use of the method according to the invention on an industrial scale is made possible on the basis of the advantages summarized above.

The method according to the invention is illustrated in more detail by means of the following non-limiting examples.

Preparation of the starting material, i.e. (5-dimethylaminomethyl-2-furylmethyl)- hydrogen sulfate ( zwitterion with formula ( III) )

Example 1

Step A

Preparation of the complex formed by sulfur trioxide

and dimethylformamide (DMF.SO^)

40 to 50 g (0.50 to 0.62 mol) of liquid SC>3 was added portionwise to 152 g (2.0 mol) of dimethylformamide while stirring and cooling at such a rate that the temperature of the reaction mixture did not exceed 20°C . The mixture was then cooled to below 5°C, after which part of the complex crystallized. After suction filtration, the complex contained 5.80 to 6.40 mmol/g of sulfur trioxide according to the analysis.

Step B

Preparation of (5-dimethylaminomethyl-2-furylmethyl) - hydrogen sulfate

To a solution containing 258 ml of acetonitrile and 22.70 g (143.2 mmol) of the filter-wet dimethylformamide-sulfur trioxide complex, prepared according to step A, was added 22.23 g (143.2 mmol) of 5-dimethylaminomethyl -2-furfuryl alcohol while stirring and cooling at such a rate that the internal temperature remained between 15 and 20°C. Then 258 ml of acetonitrile was added and the mixture was kept at 4°C overnight. The crystalline precipitate was filtered off by suction filtration, washed with acetonitrile and dried to give 17.30 g (51.3%) of the desired product, mp 179 to 181°C.

Example 2

9.93 g (124.02 mmol) of sulfur trioxide was introduced into 190

ml of anhydrous dimethylformamide under anhydrous conditions while stirring and cooling at such a rate that the internal temperature of the reaction mixture did not exceed 20°C. Then, 19.25 g (124.02 mmol) of 5-dimethylaminomethyl-2-fur uryl alcohol of formula (IV,0 ■) was added to the reaction mixture while stirring and continuously cooling at such a rate that the internal temperature remained below 20 ° C. After the addition was complete, the mixture was stirred at the same temperature for 30 minutes and kept at 0 to 4 ° C overnight. The precipitate was filtered off by suction filtration,

washed with anhydrous dimethylformamide, then with ether and dried at room temperature under reduced pressure and anhydrous conditions to give 27.10 (92.8%) of the zwitterionic compound of formula (III), melting point 179 to 181°C.

Preparation of 2-[(2-aminoethyl)-thiomethyl]-5-dimethyl-aminomethylfuran of formula (I) and its acid addition salts Example 3

Preparation of the mixed monohydrochloride-monohydrogensulphate salt of 2-[(2-aminoethyl)-thiomethyl]-5-dimethyl-aminomethylfuran base of formula (I)

A mixture containing 24.70 g (105 mmol) of the zwitterion (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulfate of formula (III) and 11.36 g (100.0 mmol) of cysteamine hydrochloride was heated in a bath held at 90 to 92°C while stirring under a dry nitrogen atmosphere for 2.5 hours. After cooling, the homogeneous melt solidified and 35.90 g of a solid was obtained with analytical data essentially corresponding to the desired mixed salt.

<C>10<H>21<C1N>2°5<S>2

Calculated: Cl 10,16; N 8.03; S04 27.53%;

Found: Cl 10.03; N 7.73; S04 27.03%

Example 4

Preparation of 2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran (the base of formula (I))

A) Preparation of a crude base of formula (I)

The melt reaction was carried out in a similar way and with the same quantities as described in example 3. After completion of the reaction, the melt was cooled, dissolved in 20

ml of water and the pH value of the solution was adjusted to 9 by adding 4N aqueous potassium hydroxide solution while cooling. After decolorization with activated carbon while stirring in a water bath maintained at 50 to 60°C, the solution was filtered and then extracted 5 times with 150 ml of dichloromethane each time. The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated. The crude base obtained (21.21 g, 94.26% calculated for the zwitterionic compound of formula (III) and 98.9% calculated for cysteamine hydrochloride) as the evaporation residue is a pale yellow oil n^ = 1.5205. A small sample of the crude base boils at 116 to 120°C/13.3 Pa.

B) Preparation of a distilled base of formula (I)

The melt reaction was carried out in a similar way and with the same quantities as described in Example 3. After the reaction was carried out, the melt was dissolved in 100 ml of water while it was hot, the pH value of the solution was adjusted to 9 by adding 4N aqueous potassium hydroxide solution and under cooling with ice, decolorized with activated carbon in a water bath maintained at 50 to 60°C and after filtration it was extracted three times with 300 ml of chloroform each time while the pH of the aqueous phase all the time was maintained at 9 by adding 4N aqueous potassium hydroxide solution. The organic extracts were combined, dried over anhydrous sodium sulfate and, after removal of the drying agent, the solution was evaporated in a water bath which was maintained. 50°C. The crude base residue was distilled, thereby obtaining 15.73 g (68.9% calculated for the zwitter-ion compound of formula (III) and 73.3% calculated for cysteamine hydrochloride) of the base of formula (I) as a main fraction, sm. p. 80 to 85°C/6.66 Pa, n^° = 1.5255.

Example 5

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

The melting turnover was carried out in a similar way and with

the same amounts as described in Example 3. The work-up and separation of the crude base was carried out according to Example 4A. The crude base weighing 21.13 g which was obtained as an evaporation residue was dissolved in 50 ml of anhydrous ethanol and ethanol containing dry hydrogen chloride was added in small portions while cooling with ice until a pH value of 2 was obtained. The mixture was kept at 0 to 4°C overnight, the crystalline precipitate was filtered off by suction filtration, washed with ice-cold anhydrous ethanol and dried at room temperature to give 23.2 g (76.9% calculated for the zwitterionic compound of formula (III) and 80 .7% calculated for cysteamine hydrochloride) of the desired product, melting point 153 to 158°C. The crude product was recrystallized from 120

ml of hot ethanol under decolorization with activated carbon, the solution obtained after filtration was concentrated to a volume of 80 ml, 3 ml of ethanol containing 80% dry hydrogen chloride was added and the mixture was kept at 0 to 4°C

over the night. The crystalline precipitate was filtered off by suction filtration and then treated as described above, whereby 17.85 g (59.1% calculated for the zwitterionic compound of formula (III.) and 62.1% calculated for cysteamine hydrochloride) of the desired product, melting point 160 to 162°C.

Example 6

Preparation of the monohydrochloride of 2-[(2-aminoethyl)thiomethyl]-5-dimethylaminomethylfuran base of formula (I)

A solution of 21.4 g (0.1 mol).2-[(2-aminoethyl)-thiomethyl]-5-dimethylaminomethylfuran base of formula (I) prepared according to Example 4B in 50 ml of methanol was added dropwise to the solution of 28.7 g (0.1 mol) of 2-[(2-amino-ethyl)-thiomethyl]-5-dimethylaminomethylfuran dihydrochloride, prepared according to Example 5, in 300 ml of methanol, then the mixture was stirred for 10 minutes and 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, melting point 111 to 112°C.

Claims (2)

1. Process for the production of 2-[{2-aminoethyl)-thiomethyl-5-dimethylaminomethylfuran with formula (I) and acid addition salts thereof, characterized by the zwitterion (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulfate of formula (III) is reacted with cysteamine or with an acid addition salt thereof, after which, if desired, an obtained acid addition salt of the base of formula (I) is separated, and/or, if desired, the base of formula (I) is liberated, purified and/or converted into another acid addition salt of the base of formula (I). 2. Method according to claim 1, characterized in that the zwitterion (5-dimethyl-aminomethyl-2-furylmethyl)-hydrogensulphate of formula (III) is reacted with cysteamine or with an acid addition salt thereof, preferably cysteamine hydrochloride, without the presence of a solvent and at a temperature between 60 °C and 90 °C.