CS259878B2 - Method of additive salt preparation with acid derived from 2(/2-aminoethyl/thiomethyl)-5-dimethylaminomethyl furane - Google Patents

Abstract

The invention relates to the acid addition salts of 2 ¢(2-aminoethyl)-thiomethyl!-5-dimethylamino-methylfuran of the formula (I) and a process for preparing same and, if desired, for transforming any of the new salts obtained to the known base of formula (I). The process comprises a) reacting the zwitterionic (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulphate of formula (III) with cysteamine or with an acid addition salt thereof, or b) treating 5-dimethylaminomethyl-2-furfuryl alcohol of the formula (IV) with sulphur trioxide or an agent suitable to introduce sulphur trioxide in the presence of a solvent, then separating and reacting the obtained (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulphate of formula (III) with cysteamine or with an acid addition salt thereof and, if desired, separating the acid addition salt of the base of formula (I) obtained by process a) or b) and/or, if desired, liberating therefrom the base of formula (I), purifying it and/or transforming it to an other acid addition salt of the base of formula (I). The compound of formula (I) and its acid addition salts are intermediates for preparing 1-{2-¢5-dimethyl-aminomethyl-2- (furylmethylthio)-ethyl!}-amino-1-methyl-amino-2-nitroethylene of the formula (II) which is a known drug against gastric and duodenal ulcers.

Description

The invention relates to a process for the preparation of an acid addition salt derived from 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran of the formula I

CH ₂ -S- (CH ₂ ) ^{n NH} 2 (>) as well as its free base.

The compound of formula I and its acid addition salts are intermediates for the preparation of 1- (2- (5-dimethylaminomethyl-2- (furylmethylthio) ethyl) -1-amino-1-methylamino-2-nitroethylene of formula II ch _{3 '} .

Z ch ₃

- With H - c - H - c H ₃

CIINOg (II), which is a known excellent cure for gastric and duodenal ulcer [Brit. J. Pharmacol. 72, 49, 55 (1981)]).

Two methods are described for the preparation of the base of formula (I) in DE Publication No. 2,734,070. These methods will hereinafter be referred to as Method A and Method B.

According to method A of Example A) (p. 37) of the above specification, a mixture containing cysteamine hydrochloride, 5-dimethylaminomethyl-2-furfurvyl alcohol of formula IV is maintained

CH ₃ and concentrated hydrochloric acid at 0 ° C for 18 hours. In this reaction, the hydrochloric acid is in a ten-fold molar excess. After working up and distillation, the base of formula I is obtained in 54% yield.

It has been found by experiments that this low yield is due to an extremely acidic environment; in particular, under these conditions the reaction is accompanied by intense tar formation.

It should be emphasized that the acid sensitivity of furan derivatives is well known in the literature (see, for example, Rodd's Chemists of Carbon Compounds, Ed. S. Coffey, Vol. IV / A, p. 91, Elsevier Co., New York, 1973). ).

The disadvantages of this method are as follows:

The reaction time required to prepare the compound of formula I is too long.

The reaction environment is extremely corrosive.

The base of formula I obtained after distillation is unstable even though it is kept in a refrigerator at a temperature between 0 and 4 ^° C; darkens after a few days. Therefore, it is not homogeneous, ie it is not suitable for further use in a relatively short time. The instability, in particular the thermal, free base of the formula I is well shown by the fact that at most 60 to 70% can be regenerated without decomposition even if the homogeneous, pure base is distilled under high vacuum and at a relatively low temperature, e.g. ° C and a pressure of 80 to 107 Pa.

For these reasons method A is not suitable for large-scale production.

Method V is only partially disclosed in Example D (p. 40), Example E (p. 41), and Example 1 (p. 48) of the above specification. According to these examples, the base of formula I is prepared in 3 steps. In the first step (Example D on page 40), 2-furylmethyl mercaptan was condensed with N- (2-bromoethyl) phthalimide to give 2- (2-phthalimidoethylthiomethylfuran) in 52.3% yield; 41) reacting these products with Mannich reaction with dimethylamine hydrochloride and formaldehyde to give 2 - [(2-phthalimidoethyl) thiomethyl] -5-dimethylaminomethylfuran, i.e. the phthaloyl derivative of the compound of formula I, in 47.3% yield; The compound of formula (I) and the yield is not given, therefore, the method V cannot be used for comparison. Therefore, the total yield of Method B, calculated for 2-furylmethylmercaptan as the starting material used in the first step, is at most 20.78% of the base of the formula AND.

For a complete comparison of method A and V, it is appropriate to monitor the starting materials of method A, i.e. the compound of formula IV, and the starting material of process B, i.e. 2-furylmethylmercaptan relative to 2-furfuryl alcohol, i.e. the conventional commercial grade up to 259878. The literature yield for the compound of formula IV is 70 percent, calculated for 2-furfuryl alcohol (J. Chem. Soc. 1958, 4728), while the literature yield for 2-furylmethylmercaptan is 60%, calculated for 2- furfuryl alcohol (Organ Syntheses Coll., Vol. 4, p. 491, John Wiley and Sons, Inc., New York, 1963).

Obviously, of the two methods known in the literature, Method A is preferable because this method yields the base of Formula I from conventional, commercially available starting materials in less steps and in a higher overall yield (i.e. 37.8%) compared to the total yield (i.e. 12.47%) of the method V. However, as mentioned above, the process V also has numerous drawbacks, especially with respect to large-scale production.

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel process for the preparation of a known compound of formula I and / or an acid addition salt thereof, which overcomes the drawbacks of the above processes and makes it possible to produce the compound of formula I and / or its acid addition salt in good yield and also on an industrial scale.

It has now surprisingly been found that the compound of formula I can be prepared more advantageously than in the above processes by the process of the invention, characterized in that the inner salt of (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulphate of formula III is reacted. ch ₂ -4.O) ~ ch. ^ 0-SOf (III?

with a cystamine or an acid addition salt thereof in the absence of a solvent at a temperature of 60 to 95 ° C and optionally separating the acid addition salt of the base of the formula I and / or optionally liberating the base of the formula I from the addition salt, is converted to another acid addition salt. Preferably, cysteamine hydrochloride is used as the acid addition salt.

It has further been found that the base of formula I, which can be directly used for the preparation of the compound of formula II, or any desired acid addition salt of the base of formula I, can easily be obtained in good quality from their new salts prepared in this way.

New starting compound of formula III can be prepared in excellent yield from 5-dimethylaminomethyl-2-furfuryl alcohol of formula IV / \ / t-СO H ^C * 3 '(IV)

by reaction with sulfur trioxide or a reagent suitable for introducing sulfur trioxide, such as a complex formed from sulfur trioxide and dimethylformamide, in the presence of a solvent.

A preferred embodiment of the process of the invention comprises melting the inner salt of a compound of formula III with an acid addition salt (e.g. hydrochloride) of cysteamine under nitrogen or under vacuum at a temperature in the range of 60-95 ° C without the addition of a solvent.

The process according to the invention can advantageously also be carried out in the presence of a solvent.

After alkalization of the aqueous melt solution obtained in the process according to the invention, the composition of which corresponds to the mixed monohydrochloride monohydrogen sulfate salt of base I, the base of formula I can be extracted with an organic solvent. The crude base of formula I obtained as the residue of an organic extract or the pure base of formula I obtained by distillation can be converted to any desired acid addition salt by addition of a suitable acid. However, the base salt of formula I formed in the process of the invention can also be converted directly without liberating the base into another acid addition salt.

As an example of the conversion of the acid addition salt of the base of formula I obtained by the process of the invention into another acid salt, the dihydrochloride can be advantageously prepared. First, by separating the base of formula I as described above, and then acidifying the solution in a lower aliphatic alcohol, for example ethanol, with a solution of dry, gaseous hydrogen chloride in a suitable lower alcohol, the dihydrochloride of the base of formula I is obtained as a crystalline precipitate.

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

Cysteamine and its salts used in the process of the invention are known compounds and are partially commercially available.

The advantages of the method of the invention can be summarized in the following.

In contrast to known method A, a large amount of concentrated mineral acid is not required for the reaction; this significantly reduces the risk of corrosion.

Due to the elimination of the strong acid, the reaction temperature of the process according to the invention can be substantially increased (for example from 0 ° C to 90 ° C) without deteriorating the product quality, thus also significantly reducing the reaction time (at least in the order of magnitude). All these factors contribute to good tar-free products.

The salts of the base of formula I prepared by the process of the invention are stable substances from which the base of formula I can optionally be released at any time, preferably shortly before use.

Some of the acid addition salts of the base of formula I prepared by the process of the invention can be used directly (i.e. without liberating the base) to prepare 1- (2- [5-dimethylaminomethyl-2259878]

- (furylmethylthio) ethyl] amino-1-methylamino-2-nitroethylene of formula II.

The volume required for the reaction is substantially reduced by eliminating the excess acid, i.e., carrying out the reaction by melting; this will increase the efficiency of the capacity of the equipment.

In the preparation of 5-dimethylaminomethyl-2-furfuryl alcohol of formula IV 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 20%) by contamination When the compound of formula IV obtained by this process is directly converted to formula I according to the method described in Example A (p. 37) No. 2,734,070, a considerable amount of contaminants, especially tar, is formed due to the high excess of acid during the reaction, even if the reaction temperature is low. Conversely, when the product of formula IV is converted to a new inner salt of the compound of formula III as described above, contaminants formed during the preparation of the compound of formula IV and adversely affecting the reaction of the compound of formula III with cysteamine hydrochloride are retained in the mother liquor left after filtering the inner salt; therefore, the reaction with cysteamine or its acid addition salt carried out in the next step is not impaired.

According to Method A, the yield of the distilled base of Formula I, calculated for the compound of Formula IV, is 54%. Since the inner salt of the compound of formula III is obtained from the compound of formula IV in 92.8% yield and the compound of formula III can be converted on the basis of formula I of the invention in 68.9% yield, the total yield of the distilled base of formula I calculated for the compound of formula IV is 63.9%, i.e. much higher than the yield of Method A.

It goes without saying that the industrial use of the process according to the invention will be made possible by the advantages mentioned above.

The process of the invention will be explained in more detail in the following examples without limiting the scope of the invention.

Preparation of the starting material, ie (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulphate (inner salt of the compound of formula III).

Example 1 step A)

Preparation of a complex formed from sulfur trioxide and dimethylformamide (DMF. SO3) up to 50 g (0.50-0.62 mol) of liquid sulfur trioxide is added in portions to 152 g (2.0 moles) of dimethylformamide with stirring and cooling at such a rate so that the temperature of the reaction mixture does not exceed 20 ° C. The mixture was then cooled to below 5 ° C and part of the complex crystallized out.

Μ ”-: · grade В)

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

To a solution containing 258 ml of acetonitrile and 22.70 g (143.2 mmol) of the wet dimethylformamide sulfur trioxide complex prepared in Step A, 22.23 g (143.2 mmol) of 5-dimethylaminomethyl-4-furfuryl alcohol are added under stirring and cooling. at such a rate that the internal temperature remains between 15 and 20 ^° C. Then 258 ml of acetonitrile is added and the mixture is kept overnight at 4 ° C. The crystalline precipitate is filtered off with suction, washed with acetonitrile and dried. 17.30 g (51.3 percent) of the desired product is obtained, mp 179-181 ° C.

Example 2

9. 93 g (124.02 mmol) of sulfur trioxide are introduced under anhydrous conditions into 190 ml of anhydrous dimethylformamide under stirring and cooling at a rate such that the internal temperature does not exceed 20 ° C. Then, 19.25 g (124.02 mmol) of 5-dimethylaminomethyl-2-furfuryl alcohol of formula IV is added to the reaction mixture with stirring and cooling at a rate such that the internal temperature remains below 20 ° C. Thereafter, the mixture was stirred at the same temperature for 30 minutes and kept overnight at 0-4 ° C. The precipitate was filtered off with suction, washed with anhydrous dimethylformamide, then with ether and dried under reduced pressure and anhydrous conditions at room temperature to give 27.10 g (92.8%) of the inner salt of the compound of formula III, m.p. 179-181 ° C.

Preparation of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran (I) and its acid addition salts

Example 3

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

A mixture of 24.70 g (105 mmol) of (5-dimethylaminomethyl-2-furylmethyl) hydrogen sulphate inner salt of formula III and 11.36 g (100.0 mmol) of cysteamine hydrochloride was heated under stirring under a dry nitrogen atmosphere for 2.5 hours. in a bath kept at 90-92 DEG C. After cooling ^P homogeneous melt solidified to give 35.90 g of a solid whose analytical data correspond substantially to the desired mixed salt.

Analysis for C10H2LCIN2O5S2

Calculated:

10.16% Cl, 8.03% N, 27.53% S04 '-,

259378

Found »:

10.03% Cl, 7.73% N, 27.03% SO 2 -.

Example 4

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

A) Preparation of the crude base of formula I

Melting is carried out in the same manner and with the same amount as described in Example 3. After completion of the reaction, the melt is cooled, dissolved in 20 ml of water and the pH of the solution is adjusted to 9 by addition of 4N aqueous potassium hydroxide solution. stirring on a water bath maintained at 50-60 ° C, the solution was filtered and then extracted five times with 150 ml of dichloromethane. The organic extracts were combined, dried over anhydrous sodium sulfate and evaporated. The crude base (21.21 g, 94.26%, calculated for the »Internal salt of the compound of formula III and 98.9%, calculated for the cysteamine hydrochloride) obtained as evaporation residue is a light yellow oil n 2o ₀ - 1.5205. A small sample of the crude base boils at 116-120 ° C / 13.3 Pa.

B] Preparation of the distilled base of formula I

Melting is carried out in the same manner and with the same amount as described in Example 3. After the reaction, the melt is dissolved in 10 ml of hot water, the pH of the solution is adjusted to 9 by addition of 4N aqueous potassium hydroxide solution, and decolourised with charcoal. in a water bath maintained at 50-60 ° C and after filtration, extracted three times with 300 ml of chloroform, while maintaining the pH of the aqueous phase constantly by adding 4N aqueous potassium hydroxide solution to 9. The organic extracts were combined, dried over anhydrous sodium sulfate and after removal of the desiccant, the solution was evaporated in a water bath maintained at 50 ^° C. The crude residue was distilled to give 15.73 g (63.9%, calculated for the inner salt of the compound of formula III and 73.3%, calculated for cysteamine). hydrochloride (base of formula I as main fraction, mp 80-85 ° C / 6.66 Pa, n _D 2 O = 1.5255).

Example 5 Ethyl) thiomethyl] -5-dimethylaminomethyl furan base of formula I

The melting is carried out in the same manner and with the same amount as described in Example 3. Treatment and separation of the crude base is carried out according to Example 4A. The crude base (21.13 g) obtained as a residue was dissolved in 20 ml of anhydrous ethanol, and ethanol containing dry hydrogen chloride was added in small portions until ice was reached, and the mixture was maintained at 0-4 ° overnight. C, the crystalline precipitate is filtered off with suction, washed with anhydrous ethanol and ice-cooled and dried at room temperature to give 23.2 g (76.9% calculated for the inner salt of the compound of formula III and 80.7% calculated for cysteamine hydrochloride) of the desired * product, mp 153-158 degrees Celsius. This crude product was recrystallized from 120 ml of hot ethanol with decolorizing charcoal, the solution was concentrated to 80 ml after filtration, 3 ml of ethanol containing * 8% dry hydrogen chloride were added, and the mixture was kept at 0-4 ° C overnight. . The crystalline precipitate is filtered off with suction and then treated as above to give 17.85 g [59.1% calculated for the inner salt of the compound of formula III and 62.1% calculated for cysteamine hydrochloride (desired product, mp 160-162 ^° C) .

Example 6

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

A solution of 21.4 g (0.1 mol) of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylammomethylfuran base of formula I, prepared according to Example 4B, in 50 ml of methanol is added dropwise to a solution of 28.7 g (0). 1 mol of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran, prepared as described in Example 5, in 320 ml of methanol, then stirred for 10 minutes and evaporated to dryness under reduced pressure. triturated with 100 ml of ether, held at 0-4 ° C for 2 hours, filtered, washed with ether and dried at 20 ° C to give 48 g (98%) of the desired product, mp-112-112 ° C.

Claims (2)

Process for the preparation of an acid addition salt derived from 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethylfuran of the formula I as well as its free base, characterized in that the inner salt of (5-dimethylaminomethyl-2-) is reacted. furylmethyl) hydrogen sulphate of formula III * with cysteamine or an acid addition salt thereof in the absence of a solvent at a temperature of 60-95 ° C and optionally the acid addition salt of the base of the formula I thus formed is separated and / or optionally the base of the formula I is liberated from the addition salt, purified and / or converted to another acid addition salt. 2. A method according to claim 1, wherein cysteamine hydrochloride is used as the acid addition salt.