HU193497B - Process for preparing sanitidine hydrogen halogenides - Google Patents

Abstract

The mfr. of the hydrochloride of 1-(2-(5-dimethyl-amino methyl-2-(furge methyl thio)-ethyl)) -amino-1-methyl amino -2-nitro ethylene is effected by reacting the monochlorohydride of 2-((2-aminoethyl)- thiomethyl)-5-dimethyl amino methyl furan with 1-methylthio-1-methylamino -2-nitroethylene in the presence of water or an organic solvent. - Alternatively the hydrochloride of 5-demethyl amino methyl -2-furfuryl alcohol is reacted with cysteamino hydrochloride at 20-120 deg.C with a catalyst. The dihydrochloride is sepd.connected to monohydrochloride and reacted with 1-methylthio-1-methylamino -2-nitroethylene and the hydrochloride sepd. out 1-methylamino -2-nitroethylene and the hydrochloride sepd. out. (Provisional Basic previously advised in week 8510)

Description

The present invention relates to a novel process for the preparation of 1- {2- [5- (dimethylaminomethyl) -2- (furylmethylthio) ethyl] -N-amino-1- (methylamino) - 2-n for the preparation of hydrogen halides of itroethylene (internationally known as ranitidine).

Due to the selective inhibitory effect of ranitidine of formula (I) on H-2 receptors, it is an excellent anti-gastric and duodenal ulcer drug. The ranitidine hydrochloride of formula (1) is used in medicine.

For the preparation of ranitidine hydrochloride of formula (I), the literature discloses the following procedures. .κΟί .. '·' · '- * ··· = Example 32 on page 75 of German Patent Publication No. 2 734 070, the hydrochloride of the compound of formula I is prepared by ) is dissolved in ethanolic hydrochloric acid and the hydrochloride is precipitated from this solution with ethyl acetate. The yield of the hydrochloride based on the base introduced was 89.6%.

No. 980,574. According to Belgian Patent No. 2 (lines 0.5-7), the crystalline form of ranitidine hydrochloride prepared in the above manner does not meet the requirements of industrial drug preparation in terms of filtration and drying.

b / Example 8 on page 8 of Belgian Patent 890,574, the hydrochloride of compound (I) is prepared by adding concentrated hydrochloric acid to an aqueous solution of the base (I), and the hydrochloride is precipitated by adding an additional amount of isopropanol. . Yield 93.9% based on input.

Thus, the starting material for both processes is the base of formula (I). This means that, in the state of the art, to form the hydrochloride of a compound of formula (I), the base of formula (I) must first be prepared in an appropriate quality, in the form and quality described below. For the preparation of this base, German Patent Publication No. 2 734 070, cited above, discloses three methods (see Examples on page 61, Examples 20 on page 66 and Examples 21 on page 67), and the most acceptable of these is the result of Example 15 on page 61, wherein the base of formula (I) is 2 - [(2-aminoethyl) thiomethyl] -5- (dimethyl) -aminomethyl) -furan may be prepared in a yield of 78% relative to furan by reacting compound (II) with 1- (methylthio) -1- (methylamino) -2-nitroethylene (III) in the presence of water for about 8 hours. overreact. Yield: 78%, m.p. 69-70 ° C. An important disadvantage of this description is that it does not describe the exact conditions of crystallization, which is crucial for the yield and quality of the base of formula (1).

Examining the course of this reaction, it was found that the procedure of Example 15 above did not provide a purity ranitidine base from which ranitidine hydrochloride could be prepared to meet the requirements of an industrial scale process and formulation.

Accordingly, it is an object of the present invention to provide a process for the preparation of the hydrohalides of the compound of formula (I) which can be easily and conveniently prepared on an industrial scale.

It has now been found that the foregoing drawbacks can be overcome by reacting a monohydrohalide of this compound with a compound of formula III instead of the base of formula II. Further, it has been found that when the starting compound is the monohydrochloride of the base (II), it is directly obtained in the pharmaceutical ranitidine hydrochloride, i.e. the hydrochloride of the base (I).

This discovery was unexpected for several reasons. On the one hand, according to the above-mentioned German Patent Publication No. 2 734 070, the compound of formula (III) is reacted with the base form of the compound of formula (TI) to give the base of formula (I). On the other hand, it is well known that the SN2-type exchange reaction of the methylthio group with amines, such as the reaction between the base II and the compound III, is generally carried out with the base form of the amines and not with their salts (Houben- Weyí, Methoden dér organizchen Chemie, E. Müller, Vol. IX, Vol. 757, and in particular 758, Georg Thieme Verlag, Stuttgart, 1955; 14, pp. 59-61; British Patent No. 2,038,322 A, page 7, Example 1.

Finally, in the prior art, it was not at all expected that the reaction of the monohydrochloride of the base (II) with the compound (III) would directly result in the preferred crystalline form of the ranitidine hydrochloride used in medicine.

SUMMARY OF THE INVENTION Accordingly, the present invention provides a novel process for the preparation of 1- {2- [5- (dimethylaminomethyl) -2- (furylmethylthio) ethyl]} amino-1- (methyl- for the preparation of hydrohalides of amino) -2-nitroethylene comprising a monohydrohalide of 2 - [(2-aminoethyl) thiomethyl] -5-dimethylaminomethyl-furan of formula II Optionally in the presence of water and / or an organic solvent, reacting with 1- (methylthio) -1- (methylamino) -2-nitroethylene of formula (III) and optionally obtaining the base of formula (I) the hydrohalide is isolated and purified.

The monohydrohalides of the compound of formula (II) used in the process of the invention are novel compounds which may be prepared from the base (II) or its dihydrohalides, either alone or in good yield, prior to reaction with the compounds of formula (III).

The dihydrohalides of the base of formula (II) are also novel compounds which are preferably prepared by treating the 5- (dimethylaminomethyl) furfuryl alcohol with a hydrohalide

The salt of -2193497 is reacted with a corresponding hydrohalide salt of cysteamine in the presence of a catalytic amount of mineral acid and optionally an organic acid (0-2 pKa).

The compound of formula (III) used in the process of the invention is known (British Patent No. 2,075,980 A, p. 3, Example 1).

In a preferred embodiment of the process according to the invention, the previously prepared monohydrohalide of the base (II) is reacted with the compound (III) at a temperature of from 20 to 90 ° C. The monohydrogen halide of the base of formula (II) is formed locally from the dihydro halide of the base of formula (II), preferably by contacting one of the halogen hydrogen molecules in the dihydrohalide molecule with an acyclic agent, preferably an alkali metal hydrocarbonate, carbonate, reacting the thus prepared monohydrohalide with the compound of formula (III). The monohydrohalides of the base of formula II can also be prepared in situ by adding a stoichiometric amount of the base of formula II to the dihydrohalide.

The process according to the invention may advantageously be carried out in the presence of water and / or an organic solvent such as methanol.

The reaction mixture obtained as a result of the reaction according to the invention consists essentially of the hydrohalide of the base of formula (I), rananidinium, from which this salt crystallizes after addition of a suitable solvent or solvent mixture such as aqueous ethanol

The ranitidine hydrohalide salts obtained by the process of the present invention are at least 95% pure. If desired, the product may be further purified by chromatography and / or fractional crystallization.

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

If the immediate aim is to prepare the hydrochloride of the base of formula (I), i.e. ranitidine, it is not necessary to prepare and isolate the base of formula (I) in a separate step to form the hydrochloride, which is particularly advantageous because the base of formula (I) in pure crystalline form is problematic in the state of the art. The process of the present invention provides directly the preferred crystalline form of ranitidine HCl.

The volume requirements of the process of the invention are very low because they do not require the addition of a solvent other than the reaction partners. Accordingly, the process of the present invention is suitable for the simple preparation of the base of formula (I) and its hydrochloride in high yield, even on an industrial scale.

The process of the invention is illustrated by the following examples.

Example 1

- (2- [5- (Dimethylaminomethyl) -2-furylmethylthio) ethyl] amino-1- (methylamino) -2-nitroethylene hydrochloride [Formula I base hydrochloride, i.e. ranitidine hydrochloride

7.2 g (0.025 mol) of 2 - [(2-qminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan dihydrochloride, 5.4 g (0.025 mol) 2 - [(2 aminoaminoethylthiomethyl] -5- (dimethylaminomethyl) furan and 7.5 g (0.05 mol) of 1- (methylthio) -1- (methylamino) -2 Nitroethylene is thoroughly mixed and heated to 60-65 ° C, water (2.5 ml) is added, followed by heating at 70 ° C for 1 hour and then at 80 ° C for half an hour. The mixture was then aspirated under vacuum at 50 ° C and 15 ml of abs. ethanol and 5 ml of abs. acetone. After cooling and onset of crystallization, the next day was cooled to 0-4 ° C, quenched and dried, yielding 5.3 g of the title compound, m.p. I36-138 ° C.

The mother liquor was evaporated in vacuo, the residue dissolved in charcoal (30 mL) and evaporated again in vacuo. To the residue, 5 ml of abs. ethanol and 5 ml of abs. acetone, cooled at 0-4 ° C overnight, decanted, dried. Another 0.32 g of the title product is obtained, m.p. 136-138 ° C. The overall yield of the title product is 47.98%. Examination of the mother liquor shows that it can be further processed to isolate about 20% of the ranitidine base, which can be converted to the hydrochloride or, if desired, to another salt.

Example 2

- {2- [5- (Dimethylaminomethyl) -2- (furylmethylthio) ethyl]} amino-1- (methylamino) -2-nitroethylene hydrochloride [Formula I base hydrochloride, i.e. ranitidine hydrochloride]

12.5 g (0.05 mol) of 2 -} (2-aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan monohydrochloride, 3 ml of water and 7.5 g (0, A thoroughly stirred mixture of 05 moles of 1- (methylthio) -1- (methylamino) -2-nitroethylene is gradually heated to 82-85 ° C in a water bath and maintained at this temperature for one hour. 10 ml of abs. ethanol, 15 mL abs. acetone and adjust the pH to 6 with concentrated hydrochloric acid. The mixture was cooled to 0-4 ° C overnight and the precipitated crystals were precipitated and dried. 4.3 g of the expected product are obtained, m.p. 135-138 ° C.

The mother liquor was evaporated in vacuo, the residue was dissolved in a mixture of 10 ml of isopropanol and 5 ml of acetone, cooled at 0-4 ° C for 2 days, then cleaved and dried. 1.8 g of the expected product are obtained, m.p. 135-138 ° C. The overall yield of the title product is 34.8%.

Example 3

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

-3193497

12.5 g (0.05 mol) of 2 - [(2-aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan monohydrochloride, 7.45 g (0.05 mol) of 1- ( a mixture of methylthio) -1-methylamino-2-nitroethylene and 2.5 ml of water was stirred at 70-75 ° C for 2 hours. After cooling, the reaction mixture was dissolved in ethanol (70 mL), clarified with activated charcoal, then Hyflo, filtered, and the pH of the filtrate (about 6.5-7) was adjusted to 5 by addition of concentrated aqueous hydrochloric acid. The solution was cooled to 0 ° C, inoculated, stirred at 0 ° C for several hours and then kept at 0-4 ° C overnight. The precipitate was filtered off, abs. washed with ethanol and dried at 50 ° C in vacuo. 6.1 g (34.8%) of the title compound are obtained, m.p. 139-141 ° C.

The mother liquor gave an additional 3.8 g (21, 7%) of the title product of similar quality, m.p. 139-141 ° C.

For example, 2 - [(2-aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan monohydrochloride, the starting material of Examples 2 and 3, may be prepared as follows:

The step

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

A mixture of 95.75 g (0.5 mol) of 5-dimethylaminomethyl-2-furfuryl alcohol hydrochloride and 64 g (0.52 mol) of 92% cysteamine hydrochloride in 9.3 ml of concentrated aqueous hydrochloric acid and After addition of 250 ml of benzene, the mixture was stirred for 4 hours at 60-62 ° C. The benzene is then decanted off, the residue is taken up in 235 ml of abs. After the addition of ethanol, the mixture was stirred for a few minutes in an 80 ° C bath, 235 ml of acetone were added and the mixture was allowed to stand at 0-4 ° C the next day. Drying and washing gave 124.5 g (86.7%) of the title compound, m.p. 161-164 ° C.

A small sample of the substance (3.8 g) in 6 ml of abs. Recrystallization from ethanol and addition of 6 ml of acetone while cooling gave 3.59 g of product after drying. 163-166 ° C.

B. / step

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

28.6 g (0.1 mol) of 2 - [(aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan dihydrochloride and 250 ml of abs. To a suspension of ethanol was added 10 g (0.1 mol) of potassium bicarbonate in 40 ml of water with stirring at 20 ° C. Stirring is continued for 50 minutes, then the precipitated potassium chloride is filtered off and the filtrate is evaporated to dryness. The residue is thoroughly worked up with ether, filtered, washed with ether and dried. Yield: 24.2 g (96%) of the title monohydrochloride, m.p. 115-116 ° C.

Example 4

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

A solution of 1.0 g (0.01 mol) of potassium bicarbonate in 4 ml of water is 2.87 g (0.01 mol) of 2 - [(2-aminoethyl) thiomethyl] -5- (dimethyl) -aminomethyl) -furan dihydrochloride, the mixture was stirred for 10 minutes and then 1.52 g (0.0102 mol) of 1- (methylthio) -1- (methylamino) -2-nitroethylene was added. the resulting mixture is heated at 40-50 ° C for 1 hour, then heated to 60 ° C over 10 minutes, then stirred at 60 ° C for 1 hour and at 70 ° C for 30 minutes. After cooling, 30 ml of abs. ethanol was added, the precipitated potassium chloride was filtered off, and the filtrate was concentrated in vacuo. The residue was dissolved in 13.8 mL of 96% ethanol and the solution was adjusted to pH a few drops with conc. The reaction solution was stirred at 0 ° C for 3 hours and then cooled to 0-4 ° C the next day. The precipitate was filtered off and further treated as described in Example 3. Yield: 1.77 g (50.5%), m.p.

138-140 ° C.

The mother liquor gave an additional 0.19 g (5.4%) of the title product, m.p. 138-140 ° C.

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

A solution of 5.0 g (0.05 mol) of potassium bicarbonate in 20 ml of water is 14.35 g (0.05 mol) of 2 - [(2-aminoethyl) thiomethyl] -5- (dimethyl) -aminomethyl) -furan dihydrochloride, the mixture was stirred for 10 minutes and then 7.45 g (0.05 mol)

- (methylthio) -1- (methylamino) -2-nitroethylene is added. The resulting mixture was heated to 40-50 ° C for one hour. and then heated to 60 ° C for 10 minutes and stirred at this temperature for one hour and then at 70 ° C for 30 minutes. After cooling, water (30 ml) was added and the solution was adjusted to pH 5 with 2N aqueous hydrochloric acid and extracted with chloroform (2 x 30 ml). The pH of the aqueous phase was then adjusted to 10 by the addition of n aqueous potassium solution and then extracted with chloroform (4 x 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was taken up in 70 ml of abs. dissolved in ethanol and clarified first with activated carbon followed by Hyflo. The filtrate is brought to pH 5.5-6 by addition of concentrated aqueous hydrochloric acid and the mixture is stirred at -0 ° C for 3 hours, if appropriate after inoculation, and then cooled to 0-4 ° C overnight. filtered and subsequently treated in the same manner as in Example 3 to give the title product (7.1 g, 39%), m.p.

139-141 ° C.

The mother liquor gave an additional 3.5 g (19%) of the title product, m.p. 139-141 ° C.

Example 6

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

-4193497

In the same manner as in Example 3, 0.01 mole of 2 - [(2-aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan monohydrochloride was prepared in an amount of 1.48 g. 1- (methylthio) -1- (methylamino) -2-nitroethylene (0.01 mol) and the mixture was stirred at room temperature for 8 hours, then allowed to stand at room temperature for 14 hours, then again at room temperature for 1 hour. stirred. Water (40 mL) was added, the pH of the solution was adjusted to 5 by the addition of 2N hydrochloric acid, and the solution was extracted with chloroform (3 x 10 mL). After separation of the phases, the aqueous phase was adjusted to pH 10 by addition of 2N aqueous potassium hydroxide solution and extracted with chloroform (4 x 20 ml).

The organic phases thus obtained were combined and, after drying, concentrated in vacuo. The remaining crude base was quadrupled in volume of abs. dissolved in ethanol, clarified and filtered. The filtrate was adjusted to pH 5 with concentrated hydrochloric acid at 0 ° C, and after inoculation at 0 ° C for 3 hours, cooled to 0-4 ° C the next day. The precipitate was washed with ethanol and dried. Yield: 1.05 g (29.9%), m.p. 139-141 ° C.

The mother liquor gave an additional 0.9 g (26%) of the title product, m.p. 138-140 ° C.

The crude base of formula (1), which acts as a distillation residue during processing, is known in the art, e.g. From 4-methyl-2-pentanone - recrystallizable, m.p. 67-68 ° C.

Claims (4)

PATENT CLAIMS 1. Process for the preparation of formula I - 1) 2- [5- (Dimethylaminomethyl) -2- (furylmethylthio) ethyl]} amino 2-[(2-aminoethyl) thiomethyl] -5- (dimethylaminomethyl) furan of formula (II) for the preparation of hydrohalides of -1-methylamino) -2-nitroethylene; By reacting 1- (methylthio) -1- (methyl-5-amino) -2-nitroethylene of formula (III), wherein the 2 - [(2-aminoethyl) thiomethyl of formula (II) ] A 5-dimethylaminomethyl-furan monohydrohalide, optionally in the presence of water and / or an organic solvent, the 1- (methylthio) -1- (methylamino) -2- reaction with nitroethylene and, if desired, isolating and purifying the resulting hydrohalide of the base of formula (I). 2. The process according to claim 1, which is a process for the preparation of 1- (2- (5- (dimethylaminomethyl) -2-furylmethylthio) ethyl) amino-1- (methyl) amino) -2-nitroethylene hydrochloride, characterized in that the monohydrochloride of 2 - [(2-amino20-ethyl) thiomethyl] -5- (dimethylaminomethyl) furan of formula II optionally water and / or organic solvent in the presence of - (III), l- (methylthio) -l- (methylamino) -2-nitroethylene reacted, if desired, ²⁵ in the compound of formula (I) thus the resulting hydrochloride is isolated and purified. 3. A process according to claim 2 wherein the monohydrochloride of 2 - [(2-amino30-ethyl) thiomethyl] -5- (dimethylaminomethyl) furan of formula II is prepared in situ. the dihydrochloride of the base of formula II. 4. A process according to claim 1 or 2, characterized in that The reaction is carried out at a temperature between 20 and 100 ° C.