HU198196B - Process for production of basic tioether and its salts - 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 present invention relates to a process for the preparation of acid addition salts of 2 - [(2-aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan of the formula I and, if desired, to the addition of any of these novel salts. To a known base of formula (I).

The compound of formula (I) and its acid addition salts are known 1- (2- [5- (dimethylaminomethyl) -2-furylmethylthio) ethyl] compounds of formula (II) having excellent gastric and duodenal ulcer activity. ]} - intermediates in the preparation of amino-1- (methylamino) -2-ni trothylene (international generic name: ranitidine).

A number of processes are described in the literature (German Patent Publication No. 2 734 070, Spanish Patent Specifications 497 514, 501 844, 502 940 and 506 422) for the preparation of the base of formula (I). In the following, these processes are referred to as A, B, C, D and E 'in the literature.

The literary A procedure is the quoted citation! Example A, page 37, and U.S. Patent No. 501,844. is described in Example 2 of Spanish Pat. Accordingly, a mixture of cysteamine hydrochloride, 5- (dimethylaminomethyl) furfuryl alcohol of formula (IV) and concentrated hydrochloric acid is maintained at 0 ° C for 18 hours and, according to Spanish description, for 48 hours. In this reaction, the hydrochloric acid is present in a molar excess of about ten times. Post-work-up distillation gives the base of the compound of formula (I) in about 54% yield as described in the German description. (The Spanish patent does not provide yield data.)

Our own experiments have shown that moderate yields are the result of an extremely strong acidic reaction medium. Under these conditions, the reaction is accompanied by strong tar formation.

Note that the sensitivity of furan compounds to acid is well known in the art. (See, e.g., Rodd's Chemistry of Carbon Compounds, Ed. S. Coffey, Stone IV / A, p. 91, Elsevier Co., New York, 1973.)

The disadvantage of this method is that

- the reaction time required to produce the product of formula (I) is very long;

- the medium is extremely corrosive;

- the base of formula (I) obtained after distillation is not stable even after storage in a refrigerator at 0-4 ° C, darkens after a few days, and then becomes unstable, and thus becomes unusable in a relatively short time. The lability of the free base of formula (I), particularly against heat, is well illustrated by the fact that, when subjected to a uniform, pure base under vacuum distillation, even at very good vacuum, at relatively low temperatures, e.g. 120-124 ° C, up to 60-70% of the pure material can be distilled without decomposition.

For all these reasons, the literature is not suitable for industrial scale export.

The literature procedure B is 2,734,070. German Federal Republic release! Example 1 on page 40 (D), page 41 (E) and page 48 is only partially illustrated. According to this, the base of formula (I) is obtained in three steps: in the first step (page 40, Example D), the furyl-2-methylmercaptan is condensed with N- (2-bromoethyl) phthalimide (yield: 52.3%). ); in the second step [41. (Example E)] The 2 - [(2-phthalimidoethyl) thiomethyl] furan thus obtained was subjected to a Mannich reaction using dimethylamine hydrochloride and formaldehyde together with 2 - [(2-phthalimidoethyl) thio. -methyl] -5-dimethylaminomethyl-furan, the N-phthaloyl derivative of the compound of formula I (yield: 47.3%); and the third step (page 48, Example 1) is dephthaloylation to give the phthalic acid hydrazide salt of compound (I). The isolation of the compound of formula (I) is neither described nor reported. Thus, the literature procedure B does not allow for comparison. Our own experiments have shown that the yield of the final step, depthaloylation, is up to 84%. Consequently, the total amount of process B in the first step is up to 20.78% of the base of formula I, based on the 2-furylmethyl mercaptan used as the starting material. The literature procedure C is described in U.S. Patent No. 497,514. Spanish Patent Specification. According to this, 5-dimethylaminomethyl-furfuryl alcohol of formula (IV) is firstly prepared from 5-dimethylaminomethyl-furfuryl-mercaptene (V) in a yield of 59.1%, followed by reacting the compound with ethyleneimine to give the distilled base of formula (I) in a yield of 79.9%. The yield of the process is about 47.2% relative to the starting material of formula IV. The main disadvantage of the process, at low yields, is that it is not feasible on an industrial scale because the ethyleneimine used is a highly toxic, carcinogenic substance. Literature Method D is disclosed in U.S. Patent No. 502,940. Spanish patent specification. According to Example 1 of this specification, furfuryl mercaptene is condensed with chloroacetamide in the presence of sodium hydride to give 2-furylmethylthioacetamide of formula VI. The yield of the reaction step is not related and the resulting compound of formula (VI) is not characterized. In this acid amide, the dimethylaminomethyl group at position 5 is introduced by Mannich reaction as in Example 3, so that 2 - [(carboxamidomethyl) thiomethyl] -5- (dimethyl) aminomethyl) furan. The yield of the Mannich reaction is not yet reported and the resulting compound of formula VII is not characterized by any physical data. The final step of the process is illustrated in Example 5. Accordingly, the compound of formula (VII) is reduced with lithium aluminum hydride to form the base of formula (I). No return on this step either

EN 198196 Β. It should be noted, however, that process D employs metal hydride and complex metal hydride in two steps, which are highly sensitive, flammable and explosive reagents, so that the industrial feasibility of the process is highly doubtful.

In Step E of the literature (Spanish Patent No. 506,422), 5-chloromethylfurfural is reacted with formic acid and dimethylformamide to give 5- (dimethylaminomethyl) 56% in yield. -2-chloromethyl-furene. (However, this compound is not characterized). The product obtained is condensed with cysteamine in the presence of sodium ethanolate to give the base of formula (I). The yield of the second step was 70.1%. (Combined yield of first and second steps: 39.3%.) It is noted that the starting material of the process is 5-chloromethyl-furfural according to the literature [Bér. 47, 874] can be obtained from cane sugar in a yield of about 20% by a very delicate and fast operation. The product is not in commercial batches - not commercially available. Based on the foregoing, process E is also not considered an industrial process.

Accordingly, 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 acid addition salts thereof which is free from the above-mentioned processes known in the state of the art. To prepare a compound of formula (I) and / or acid addition salts thereof.

It has been found that the compound of formula (I) can be prepared much more advantageously than the above-described methods by obtaining an acid addition salt of cysteamine from a novel 5-dimethylaminomethyl-furfuryl alcohol of formula (IV). (5-dimethylaminomethyl-furyl-2-methyl-ethyl) -hydrogen sulphate zwitterion, and it has now been found that ranitidine can be easily obtained in good quality from the new salts of the base of formula (I) a base of formula (I) or a desired acid addition salt thereof.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of the mixed acid addition salts of 2 - [(2-anunoethyl) thiomethyl] -5- (dimethylaminomethyl) furan of formula (I) wherein one of the components is ( The mono-bisulfate salt of the base of formula (I) and, if desired, the conversion of any of the resulting new mixed salts to a known base of formula (I), which comprises [5- (dimethylaminomethyl) - The furyl-2-methyl] -hydrogen sulfate zwitterion is reacted with an acid addition salt of cysteamine, and if desired the acid addition salt obtained is isolated and / or the base of formula I is liberated.

In a preferred embodiment of the process of the invention, the zwitterion (III) is melted with an acid addition salt (such as its hydrochloride) of cysteamine at a temperature between 60 and 95 ° C, without solvent, under nitrogen or under vacuum. The aqueous solution of the melt thus obtained, which corresponds to the monohydrochloride monohydrogen sulphate salt of the base of formula (I), can be extracted with an organic solvent to basify the base of formula (I). The crude base of formula (I) obtained by distillation of the organic extract or the pure base obtained by distillation thereof may optionally be converted into the desired acid addition salt of the base (I) by addition of the appropriate acid component. However, the salt of the base of formula (I) formed in the process of the invention can be converted directly into another acid addition salt of the base of formula (I) without releasing the base.

Advantageously, the process according to the invention can be carried out in the presence of solvents.

An example of converting the boronic acid addition salt of the base of formula (I) to another acid addition salt of the process according to the invention is that the dihydrochloride is preferably prepared by first treating the base (I) with a lower alkanol, For example, a solution of ethanol in ethanol is acidified with the corresponding alkanol containing dry hydrochloric acid gas to give the dihydrochloride of the base (I) as a crystalline precipitate.

One starting material for the process of the present invention is the novel [5- (dimethylaminomethyl) furyl-2-methyl] bisulfite zwitterionic compound of formula (III), which may be prepared by reacting the 5- (dimethyl) -aminomethyl) furfuryl alcohol solvent e.g. in the presence of dimethylformamide or acetonitrile with sulfur trioxide or with a sulfur trioxide delivery agent e.g. reacting the sulfur trioxide with a complex with dimethylformamide, pyridine or dioxane.

Cysteamine salts used as another starting compound for the process of the invention are known, in part commercially available compounds.

The advantages of the process of the invention are summarized below.

1. Contrary to the best method known in the literature (Method A), large amounts of concentrated mineral acid are not required for the reaction, and thus the risk of corrosion is greatly increased by zeocene.

2. It is largely due to the elimination of the strong acid that the reaction temperature can be increased significantly (e.g. from 0 ° C to 90 ° C) without causing any degradation of the desired product, and thus the reaction time is very significant (at least one order of magnitude). shortened. All of this contributes to providing high quality tar-free target products.

HU 198196 Β

3. The salts of the base of formula (I) obtained by the process of the invention are well-defined, stable substances which, if desired, can be liberated at any time shortly before use, in order to release the base (I).

4. Each of the acid addition salts of the base of formula (I) obtained by the process of the invention can be used directly (without liberating the base) for the preparation of ranitidine.

5. Elimination of the excess acid, that is, the reaction in bulk form substantially reduces the volume required for the reaction, thus increasing the utilization of the equipment required to carry it out.

6. According to Method A, the yield of the distilled base of formula (I) is about 54% of the compound of formula (IV). After the preparation of the zwitterionic compound of formula (III) from the compound of formula (IV) in 92.8% yield, the resulting zwitterionic compound of formula (III) can be converted to the base of formula (I) by 68.9% by the process of this invention. Thus, the total yield of distilled base of formula (I) to compound of formula (IV) is 63.9%; so it is significantly better than the yield of the literature A procedure. It will be readily apparent that the advantages summarized above permit the industrial application of the process of the invention.

The process of the invention will be described in detail in the following embodiments:

Example 1

Preparation of a mixed salt of 2 - [(2-aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan / base of formula (I) / monohydrochloride monohydrogen sulphate

24.70 g (105 mmol) of 5- (dimethylaminoethyl) -2-furylmethyl (bisulfate) zwitterion (III) and 11.36 g (100.0 mmol) of cysteamine. The hydrochloride mixture was heated under a stream of dry nitrogen in an oil bath at 90-92 ° C for 2.5 hours, stirring occasionally. After cooling, the homogeneous melt solidifies. It weighs 35.90 g and is approximately equivalent to the title salt.

Analysis: Calculated for C 10 H 21 ClN 2 O 5 S 2:% Cl 10.16; N, 8.03;

SO4 - 27.53;

found:% Cl 10.03; N, 7.73;

SO <- 27.03.

The starting material of this example, the [5- (dimethylaminomethyl) -2-furylmethyl] bisulfite zwitterion (III), can be prepared, for example, as follows:

Sulfur trioxide (9.93 g, 124.02 mmol) was added to anhydrous dimethylformamide (190 mL), with the exclusion of moisture, at a rate such that the internal reaction temperature did not rise above 20 ° C. Subsequently, while cooling and stirring, 19.25 g (124.02 mmol) of 5- (dimethylaminomethyl) -2-furfuryl alcohol are added at such a rate that the internal temperature remains below 20 ° C. After the addition was complete, the mixture was stirred at the same temperature for half an hour, kept at 0-4 ° C the next day, then filtered off with suction, washed first with anhydrous dimethylformamide and then with ether, and dried under vacuum at room temperature. 27.10 g (92.8%) of the title compound (III) are obtained, m.p. 179-181 ° C.

Example 2

Preparation of 2 - [(2-Aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan (base of formula I)

A) Preparation of crude base of formula (I)

The bulk reaction is performed as described in Example 1 and in amounts. After the reaction, the cooled melt was dissolved in water (20 mL), adjusted to pH 9 with ice-cold 4N aqueous potassium hydroxide solution, and clarified with charcoal in a water bath at 50-60 ° C. After filtration, the aqueous solution was extracted with dichloromethane (5 x 150 mL). After combining, the organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated in vacuo. The pale yellow oily residue weighed 21.21 g (94.26% based on the zwitterion compound III and 98.9% based on cysteamine hydrochloride), no ²⁰ = 1.5205. The small sample of the crude base has a boiling point of 116-120 ° C / 13.3 Pa.

B) Preparation of distilled base of formula (I)

The bulk reaction is performed as described in Example 1 and in amounts. After completion of the reaction, the melt was dissolved while still warm in 100 ml of water, the pH of the solution was adjusted to 9 with ice-cold potassium hydroxide solution and clarified in a water bath at 50-60 ° C. After filtration, it is extracted three times with 300 ml of chloroform each time while maintaining the pH of the aqueous solution at 9 by the addition of 4N aqueous potassium hydroxide solution. After combining, the organic phase is dried over anhydrous sodium sulfate and, after removal of the desiccant, the solvent is evaporated in a water bath at 50 ° C under vacuum. The residual crude base is fractionally distilled. Főpérlatként 15.73 g (68,9X (III) with a compound of formula zwitterion and 73.3% based on cysteamine hydrochloride) base of the title compound, boiling point 80-85 C '/ 6.66 mm Hg no ²⁰ = 1 , 5255th

HU 198196 Β

Example 3

Preparation of 2 - [(2-Aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan / base / dihydrochloride of formula (I)

The bulk reaction is carried out as described in Example 1 and in amounts, followed by work-up and isolation of the crude base as in Example 2A. The crude base (21.13 g) obtained as a residue was dissolved in 50 ml of anhydrous ethanol, followed by the addition of ethanol containing dry hydrochloric acid gas in small portions under ice-cooling until a pH of 2 was achieved. The next day, the reaction mixture was kept at 0-4 ° C. The precipitated crystalline precipitate was filtered off, washed with ice-cold anhydrous ethanol and dried at room temperature. 23.2 g (76.9% of the zwitterion III compound and 80.7% of the title amine hydrochloride) are obtained, m.p. 153-158 ° C. This crude product was recrystallized from hot ethanol (120 mL) with activated charcoal clarification. After filtration, the solution was concentrated in vacuo to 80 mL, treated with 3 mL of 8% ethanolic hydrogen chloride gas and kept at 0-4 ° C overnight. The crystalline precipitate is filtered off with suction and proceeded as described above. 17.85 g (59.1% of zwitterionic compound 111 and 62.1% of cysteamine hydrochloride) are obtained in the form of the title dihydrochloride, m.p. 160-162 ° C.

Claims (4)

PATENT CLAIMS A process for the preparation of mixed acid addition salts of 2 - ((2-aminoethyl) thio-thioethyl) -5- (dimethylaminomethyl) furan of formula (I) in which one of the components is a base of formula (I) a salt of mono-bisulfate and optionally any of the resulting new mixed salts to a known base of formula (I), characterized in that the [5- (dimethylaminomethyl) -2-furylmethyl (III) The hydrogen sulfide zwitterion is reacted with an acid addition salt of cysteamine and, if desired, the acid addition salt obtained is isolated and / or liberates the base of formula (I). Process according to claim 1, characterized in that the reaction partners are reacted without the addition of a solvent. Process according to claim 1 or 2, characterized in that the reaction is carried out at a temperature of 60 to 95 ° C. 4. Process according to any one of claims 1 to 3, characterized in that the acid addition salt of cysteamine is cysteamine hydrochloride.