HU193496B - Process for production of basic tioether and it salts i - Google Patents

Abstract

The present invention relates to a novel process for the preparation of the hydrochlorides of 2- [2-aminoethylthio-methyl] -5-dimethylaminomethyl-furan of formula (I) and, if desired, any of the salts of the salts obtained. known to be converted to a base of formula (I), comprising the 5-dimethylaminomethylfurfuryl alcohol hydride of formula (III) and the hydrochloride of cysteamine at a temperature of from 20 ° C to 120 ° C; without addition of solvent, optionally in the presence of an inert formulation diluent, optionally under a slight vacuum, with a catalytic amount of mineral acid and, optionally, with a catalytic amount of mineral acid and / or a catalytic amount of the above reaction conditions; / 0-2 pKa / organic acid in the presence of a compound, and, if desired, separates the dihydrochloride obtained by any of the processes a / b. and, if desired, the base of formula (I) is liberated and / or, if desired, converted into the monohydrochloride of the base of formula (I) H6n-HC <7ach- (c <-nh2 HjC2O1). h3cx / h3c CH2OH Sitting) -1-

Description

The present invention relates to a novel process for the preparation of 2 - [(2-aminoethylthiomethyl) -5-dimethylaminomethyl] furan and its hydrochlorides of formula (I).

The compound of formula (I) and the acid addition salts thereof are known, having excellent gastric and duodenal ulcers, the compound of formula (II) 1- {2- [5- (Dimethylamino-methyl) -2-furylmethyl-thio] -ethyl] -amino-1 ( me til amino) 2 nitroethylene (international generic name: ranitidine). The hydrochlorides of the compound of formula (I) are novel compounds.

Two processes for the preparation of the base of formula (I) are described in German Patent Publication No. 2 734 070. In the following, these procedures are referred to as "Literary A and" Literary B.

Literature Method A is described in Example A / on page 37 of the cited publication. Accordingly, a mixture of cysteamine hydrochloride, 5 (di-methylamino-methyl) -furfuryl alcohol (a) and concentrated hydrochloric acid is maintained at 0 ° C for 18 hours. In this reaction, the hydrochloric acid is present in a molar excess of about ten times. Post-distillation yields about 54% of the base of the compound of formula (I).

Our own experiments have shown that the very moderate yields are the result of an extremely strong acidic reaction medium. Under the circumstances, the reaction is accompanied by strong tar formation. Note that the acid sensitivity of furan compounds is well known in the art. See, e.g., Rodd's Chemistry of Carbon Compounds, Ed. S. Coffey, Vol. IV / A. 91, ElsevierCo., New York, 1973

The disadvantage of this method is that the product has a "lead time" very long;

the medium is extremely corrosive; the base of formula (I) obtained after distillation, even when stored in a refrigerator at 0 to 4 ° C, becomes unstable after a few days and becomes unsuitable for further use in a relatively short period of time. Particularly the thermal stability of the free base of formula (I) is illustrated by the fact that, when subjected to a uniform, pure base under vacuum distillation, even under very good vacuum, at relatively low temperatures (e.g. on), not more than 60 and 70% pure material without distillation.

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

Procedure B is described in part in Example D, page 40, page E, page 41, and page 48, page 48 of German Offenlegungsschrift 2 734 070. Accordingly, in three steps, the base of formula (I) is condensed in the first step (page 40, Example D) by condensation of the furyl 2 methyl mercaptan with N (2-bromoethyl) phthalimide (52.3% yield); In a second step (page 41, Example E), the resulting 2 - [(2-phthalimidoethyl) thio methyl] -furan was obtained by Mannich reaction with the combined action of dimethylamine hydrochloride and formaldehyde. methyl] 5-dimethylamino methyl furan, i.e. the N-phthaloyl derivative of the compound of formula (I) (yield 47.3%); and in a third step (page 48, Example 1), dephallylation yields the hydrazide salt of the compound of formula (I). The isolation of the compound of formula (I) is neither described nor reported. Thus, the literature procedure 8 does not allow for comparison. Our own experiments have shown that the final step, the yield of up to 84% of deftaloylation, can be taken. Based on this, the total yield of process B, based on the 2 furylmethyl mercaptan used in the first step, is 1.78%.

When comparing Literature Methods A and Literature B to Autumn, it is expedient for complete comparison to use both the starting material of Literature A, i.e., the compound of Formula III, and the starting material of Office B, i.e., furyl-2-mercaptan. Commonly available commercially available raw material, i.e., furfuryl alcohol, is known from the literature (J. Chem. Soc. 1958, 4728) as having a yield of furfuryl alcohol of 70%, known as furfuryl alcohol from furfuryl alcohol. train to 60%. (Organic Syntheses Coll. Vol. 4, p. 491, John Wiley and Sons, Inc., New York, 1963)

Obviously, of the two methods known in the literature, the clear A method is the preferred one, since this way they are commercialized in less bulk and with a better overall yield (37.8% versus 12.47% for the B method). from the starting material to the base of formula (I). However, it has been pointed out above that process A is also disadvantageous mainly in terms of industrial size.

Accordingly, it is an object of the present invention to provide a process for the preparation of the compound of formula (I) and / or its hydrochloric salts which is free from the above-mentioned prior art processes and which is easy to to prepare the compound of the formula I and / or its hydrochloric acid salts.

It has been found that the foregoing drawbacks can be overcome by reacting the hydrochloride of the compound of formula (III) with the hydrochloride of cysteamine, and it is found that the hydrochloride of the compound of formula (I) thus obtained can be readily and highly purified if desired. The base of formula (I), or a portion of the resulting salts, can be used to make high-quality ranitidine directly.

SUMMARY OF THE INVENTION The present invention relates to a novel process for the preparation of the hydrochloride hydrochloride of 2 [(2-aminoethyl / thio-methyl] / dimethylamino-methyl / furan of formula (I)

-2193496 and, if desired, converting any of the resulting salts into a base of formula (I) which comprises the hydrochloride of 5-dimethylaminomethyl-furfuryl alcohol of formula (III) and cysteamine. hydrochloride at 20 to 120 ° C without the addition of a solvent, optionally in the presence of an inert organic diluent, optionally under mild vacuum, under a / catalytic amount of a mineral acid and optionally with a pH of 0-2 pKa / organic or with an amount of a mineral acid and optionally an organic acid having a value of 0-2 pKa / organic acid, optionally isolating the dihydrochloride salt obtained by any of the processes a / or b) and liberating the base of the formula (I) and or, if desired, the monohydrochloride of the base of formula (I) According to process a /, the hydrochloride of the compound of formula (III) is preferably prepared in the presence of a catalytic amount of a mineral acid, preferably hydrochloric acid, in the absence of a solvent, optionally in the presence of an inert organic diluent, optionally under a slight vacuum. reacted. The reaction is carried out at a temperature of from 20 to 120 ° C, preferably from 20 to 75 ° C.

Part of the catalytic amount of mineral acid may be replaced by an organic acid of similar strength (0-2 pKa), preferably a sulfonic acid such as p-toluenesulfonic acid. The use of organic diluents which do not dissolve any of the starting compounds (salts) may be particularly advantageous in the industrial scale implementation of the process of the invention. Suitable diluents include aliphatic or aromatic hydrocarbons or halogenated aliphatic hydrocarbons. Preferred diluents for the reaction are, for example, benzene, toluene, dichloromethane or petroleum ether boiling at 60-100 ° C. The acid addition salt formed in the process of the invention can be isolated, for example, by cooling the reaction mixture with a lower alcohol such as ethanol or a mixture of a lower alcohol and a lower aliphatic ketone such as acetone to give the base of formula (I). its acid addition salt usually precipitates in crystalline form and can be isolated by filtration. For example, the dihydrochloride of the base of formula (I) can be obtained in 87% yield.

However, the dihydrochloride salt of the base of Formula I can be liberated by the addition of a suitable alkaline material, for example, by addition of an alkali metal hydroxide, either locally or after isolation of the salt. can be converted directly to the monohydrochloride salt of the compound of formula (I) without releasing the base The new monohydrochloride of the base of formula (I) can also be used directly to produce ranitidine

According to the process b /, the mixture of the compound of formula (III) and the hydrochloride salt of cysteamine is preferably reacted under the reaction conditions with a hydrochloric acid and an organic acid having a similar strength to hydrochloric acid, preferably a phosphoric acid halide / e.g. oxide trichloride or an inorganic or organic acid halide such as thionyl chloride, acetyl chloride, p-toluenesulfonic acid chloride or aluminum chloride is added in a catalytic amount followed by the addition of the components for 2 to 3 hours at 50-90 ° C. In the absence of solvent, it is melted under a slight vacuum. The isolation and conversion of the resulting acid addition salts can be carried out as described in process a /. In this manner, the dihydrochloride of the base (I) is obtained in a yield of 82-92%.

The starting compounds of the present invention are known compounds / hydrochloride of 5- (dimethylaminomethyl) furthuryl alcohol, for example described in J. Am. Chem. Soc. 69, 464 (1947). Cysteamine hydrochloride is commercially available.

The advantages of the process according to the invention may be summarized as follows.

1. The known process does not require a large amount of concentrated mineral acid for the reaction, so that the risk of corrosion is greatly reduced.

2. It is largely due to the reduction of the excess of strong acid to the catalytic level that this time the temperature can be increased substantially (e.g. from 0 C 'to 90 C') without damaging the quality of the desired product, and thus the reaction time is very significantly (at least one order of magnitude ) shortens. This is clear with the reduction in lead time. All of this contributes to getting good quality tar-free target products.

3. The hydrochlorides of the compound of formula (I) prepared according to the present invention are well-defined, stable, non-volatile substances which, if desired, may be liberated at any time shortly before use to provide the base of formula (I).

The hydrochlorides of the compound of formula (I) obtained by the process of the invention can be used, in part, directly (without liberating the base) to produce ranitidine.

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

It will be readily apparent that each of the advantages summarized above also contributes to the industrial applicability of the process of the invention.

The following examples illustrate the process of the invention

-3193496

Example 1

Preparation of 2 - [(2-Aminoethyl) thiomethyl] -5-dimethylaminomethyl-furan dihydrochloride

A mixture of 9.08 g (0.08 mol) of cysteamine hydrochloride and 15.32 g (0.08 mol) of 5- (dimethylaminomethyl) furfuryl alcohol hydrochloride is melted at 70-75 ° C with stirring. 75 ml of concentrated hydrochloric acid and stirred for one hour at 80 ° C and then for 20 minutes at 90 ° C, all at a slight vacuum of 40,000 to 60,000 Pa. Allow to cool to 70C, add 15 mL of abs. ethanol, kept at room temperature for 2 hours, mixed with 15 ml of abs. acetone and cooled to 0-4 ° C overnight and the precipitated crystalline precipitate was washed with ethanol-acetone (1: 1) and dried to give the title product (20.19 g, 87.2%), m.p. .. 160-162 C.

Example 2

2-] (2-Aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan dihydrochloride

A mixture of 4.54 g (0.04 mol) of cysteamine hydrochloride and 7.66 g (0.04 mol) of 5- (dimethylaminomethyl) furfuryl alcohol hydrochloride is melted at 70-75 ° C with stirring, 18 ml of concentrated hydrochloric acid was heated to 80 ° C and after stirring at 0.5 ° C for 0.5 hour, 0.5 g of p-toluenesulfonic acid was added, followed by stirring at 90 ° C for 20 minutes, all the way under a slight vacuum. After cooling, the reaction mixture was worked up as in Example 1. Yield: 9.83 g (85.4%), m.p. 158-160 ° C \

Example 3

Preparation of 2 - [(2-Aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan dihydrochloride.

The procedure was the same as in Example 2, but using 0.3 ml of 85% phosphoric acid instead of p-toluenesulfonic acid. Yield: 9.8 g (85.3%) of the title product, m.p.

Example 4 Preparation of [(2-Aminoethyl) thio methyl] -5- (dimethylaminomethyl) furan (compound of formula I)

To a mixture of 38.6 g (0.134 mol) of 2 - [(2-aminoethyl) thio-methyl] -5-dimethylaminomethyl-furan dihydrochloride in 19 ml of water at 5 to 20 ° C with shaking 29 ml. % sodium hydroxide was added and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried over anhydrous potassium carbonate, filtered, and the solvent was evaporated from the filtrate and the residue was fractionated in vacuo with a Vigreux plug. Yield: 22.88 g (79.49%) of the title base, b.p. 116-120 ° C / 13.3322 Pa.

Example 5

Preparation of 2 - [(2-Aminoethyl) thiomethyl] -5- (dimethyl a minomethyl) furan dihydrochloride

A mixture of 9.08 g (0.08 mol) of cysteamine hydrochloride and 15.32 g (0.08 mol) of 5- (dimethylaminomethyl) -furfuryl alcohol hydrochloride is melted at 78 ° C and 0.2 ml of thionyl chloride is added. Stir at 80 ° C for 10 minutes, then stir under a gentle vacuum at 80 ° C for 50 minutes and at 90 ° C for 20 minutes. Allow to cool to 70 ° C, 20 ml of abs. ethanol was added, boiled, 20 ml of abs. ethanol, followed by 40 ml of acetone and cooled to 5 ° C overnight. The precipitated crystalline precipitate was washed with ethanol-acetone (1: 1) and dried. Yield: 19.6 g (85.36%), m.p. 156-158 ° C.

Example 6

Preparation of 2 -] (2-Aminoethyl) thio methyl] -5 (dimethyl minino methyl) furan dihydrochloride

The procedure was the same as in Example 5, except that 1 g of aluminum chloride was used instead of thionyl chloride. Yield: 21.1 g (91.9%) of the title product.

Example 7

Preparation of 2 - [(2-Aminoethyl) thiomethyl] -5-dimethylaminomethyl-furan dihydrochloride

19.0 g (0.167 mol) of cysteamine hydrochloride and

A mixture of 32.4 g (0.169 mol) of 5-dimethylaminomethyl-fur-furyl alcohol hydrochloride was melted at 67 ° C and 1.0 ml of concentrated hydrochloric acid was added. The temperature rose to 90 C ^ü 16 minutes, then we added an additional 0.5 ml of concentrated hydrochloric acid, stirred at this temperature for 40 minutes, then 80 ° C was allowed to cool, and treated with 95 ml of abs. ethanol, the crystallization mixture is thoroughly stirred, cooled, crystallized, abs. washed with ethanol, dried to give 40.1 g (based on cysteamine hydrochloride)

83.7% of theory, m.p. 159-161 ° C.

Example 8

2-] (2-Aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan dihydrochloride

A mixture of 14.7 g (0.13 mol) of cysteamine hydrochloride, 23.0 g (0.12 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride and 5 ml of concentrated aqueous hydrochloric acid was stirred for a few minutes. Heat to 60 ° C. After stirring for about 10 minutes, a melt is formed; it was allowed to cool to room temperature, stirred at room temperature for 6 hours and then kept at room temperature for 60 hours. The crystalline mixture was suspended in ethanol (100 mL), dissolved by boiling, cooled rapidly with stirring, cooled to 0-5 C for 1 hour, filtered and the precipitate washed with ice-cold ethanol. Yield: 25 g (72.5%), m.p. 163-165 ° C after recrystallization from 96% ethanol.

Example 9

Preparation of 2 - [(2-Aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan dihydrochloride

A mixture of 29.4 g (0.24 mol) cysteamine hydrochloride and 45.96 g (0.24 mol) 5- (dimethylaminomethyl) -2-furfuryl alcohol hydrochloride was melted in a bath at 7075 C with stirring. At an internal temperature of 60 ° C, 3.6 ml of concentrated aqueous hydrochloric acid are added dropwise with stirring to ca. 10 minutes and then at 60 ° C for 3 hours. and then stirred at 70 ° C for one hour

At -4193496 60 ml of absolute ethanol were added. The mixture was allowed to cool to 40 ° C, then 60 ml of acetone were added, stirred at room temperature for 2 hours and then stored in a refrigerator overnight. At 6 ° C. The crystalline precipitate is filtered off, washed with ethanol / acetone and dried. Yield: 55.4 g (80.4%), m.p. 158,160 C. This product is recrystallized from three volumes of 96% ethanol by purification with anesthesia to give an analytically pure product, m.p. 164 165 C

Example 10

Preparation of 2 - [(2-Amino-ethyl / thio-methyl] -5 / dimethyl as the methyl / furan dihydrochloride

A mixture of 9.8 g / 0.08 mol / cysteamine hydrochloride, 1 ml water and 15.32 g / 0.08 mol / 5 / dimethylaminomethyl / -2-furfuryl alcohol hydrochloride was heated in a 45 ° C water bath with stirring. C ^u internal temperature reached - then a clear melt is obtained - * 10 minutes 0.6 ml of concentrated aqueous hydrochloric acid and 0.5 ml of ethyl chloro sulfite solution / preparation see below / was added, and the mixture was for 3 hours at 60 C temperature and stir for 1 hour at 70 ° C. 20 ml of abs. ethanol was added, after which it was allowed to cool to 40 ° C, 20 ml of acetone were added, the mixture was stirred at room temperature for 2 hours and then left at 5 ° C for the next day. In the following, the procedure of Example 9 above is followed. Yield: 19.48 g (84.8%), m.p. 158 160 C ".

The ethyl chlorosulphite solution was prepared by adding 10 ml of abs. Thionyl chloride (2.8 ml) was added dropwise to ethanol and the mixture was stirred for 30 minutes at 10 ° C.

/ /. Example 12 Preparation of [12 Amino ethyl / thio methyl] 5 / dimethyl minin methyl / furan dihydrochloride

A mixture of 95.75 g / 0.5 mol / 5 / dimethylamino methyl / furfuryl alcohol hydrochloride and 64 g / 0.52 mol /% cysteamine hydrochloride was added internally in autumn after addition of 9.3 ml of concentrated aqueous hydrochloric acid and 250 ml of benzene. for 60 hours

After stirring at C, the benzene was decanted, the residue was taken up in 235 ml of abs. After adding ethanol, stir for a few minutes in an 80 cos bath, add 235 ml of acetone and mix thoroughly the next day.

Leave to stand at C After drying and washing, the title compound is obtained after drying at 124.5 g (86.7%), m.p. 161

164 C '.

Recrystallization of a small sample of the material (3.8 g / 6 ml) from ethanol and addition of 6 ml of acetone while cooling gave 3.59 g of product after drying. Mp 163 166 C

Example 12 Preparation of [12 Amino-ethyl / thio-methyl] -5 / dimethyl as the methyl / furan dihydrochloride

In all of the above Examples 11, but substituting benzene for the same amount of dichloroethane, 89% of the title compound are obtained today, m.p. 157-161 ° C.

Example 13 Preparation of [12 Amino-ethyl / thio-methyl] -5 / dimethyl as the methyl / furan dihydrochloride

In all of the procedures of Example 11 above, the same amount of petroleum ether (70-80 C ') was used in place of benzene to give the title compound in 83% yield, m.p. 160-162 ° C.

/ Example 4 [/ Amino ethyl / thio methyl] 5 / dimethylaminomethyl / furan monohydrochloride

2.86 g / 0.01 mol / 2 [aminoethyl / thio methyl] / dimethylamino methyl / furan dihydrochloride and 25 ml of abs. A solution of 1.0 g / 0.01 M potassium bicarbonate in 4 mL of water was added to the slurry of ethanol with stirring at 20 ° C. Stirring is continued for 30 minutes, then the precipitated potassium chloride is filtered off and the filtrate is evaporated to dryness. Today, the radars are thoroughly worked up with ether, filtered, washed with ether and dried. Yield: 2.42 g (96%) of the title mono hydrochloride, m.p. 115 116 C.

Example 15 Preparation of [(Amino-ethyl / thio-methyl] -5 / dimethylaminomethyl / furan monohydrochloride

To a solution of 21.4 g / 0.1 mol / 2 [aminoethyl / thio methyl] -5 / dimethylamino methyl / furan in 50 mole of toluene was added dropwise with stirring, stirring for a few minutes and then evaporating to dryness in vacuo. The residue was thoroughly worked up with 100 ml of ether, kept at 0 ° C for 2 hours, then filtered, the precipitate was washed with ether and dried at 20 ° C to give the title mono hydrochloride (48 g, 89%), m.p. 111-112 ° C

Claims (3)

A process for the preparation of the hydrochlorides of 2 - [(2-aminoethyl / thio-methyl] - 5-dimethylamino-methyl / furan of formula (I) by reaction of formula (III) with cis-amine hydrochloride and, if desired, To the base of formula (I), characterized in that the hydrochloride of the 5 / dimethylaminomethyl / furfuryl alcohol of formula (III) and the cysteamine hydrochloride at a temperature between 20 ° C and 120 ° C without addition of a solvent, if desired in the presence of an inert organic diluent, optionally with mild vacuum, a catalytic amount of mineral acid and optionally / 0 2 pKa / organic acid or b / a catalytic amount of mineral acid under the above reaction conditions and optionally / 0 2 pKa / in the presence of a compound which also contains an organic acid and optionally any of the processes a / or b / the dihydrochloride salt obtained is isolated and, if desired, the hydrochloride salts are liberated to form the base (I) and / or converted to the monohydrochloride -5193496 2. A process according to claim 1, wherein the organic acid is a p-toluenesulfonic acid having a similar strength to a mineral acid. The process of claim 1, wherein: and using thionyl chloride as the catalytic amount of mineral acid.