NO179208B - Process for Preparation of 1-α2 - [(5-Diamethylaminomethyl-2-furyl) -methylthio] -ethyl-amino-1-methylamino-2-nitroethylene (ranitidine) - Google Patents

Description

The invention relates to a new process for the production of 1-{2-[(5-dimethylaminomethyl-2-furyl)-methylthio]-ethyl}-amino-1-methylamino-2-nitroethylene with formula (I)

(generic name: ranitidine).

It is known that the compound of formula (I), which is

a highly effective H-2 receptor antagonist, is the active ingredient in several excellent medicines that can be used against ulcers in the stomach and duodenum.

The preparation of the compound of formula (I) in three different ways was first described in British Patent Specification No. 1,565,966. However, these methods had to be carried out through a large number of steps and gave a rather low yield, and in addition cumbersome purification methods are necessary to obtain a pure product.

After the compound of formula (I) had become an important drug, new methods for its preparation were developed in addition to those mentioned above. IN

Today, more than 10 ranitidine methods are known, all of which, however, have disadvantages. Some of the methods start from the corresponding thiol derivative (see, for example, US Patent Nos. 4,497,961 and 4,440,938), however, these methods require a reactant that contains a nitro group (e.g., an aziridine derivative), and which is quite difficult to produce.

An ingenious method was published in the European patent applications no. 0.055.625 and 0.219.225, where the dimethylaminomethyl group bound in the 2-position of the furan ring was introduced in the final step of the synthesis. The disadvantage of these methods was that the last step resulted in a surprisingly low yield due to various side reactions.

Among various other types of synthesis, the Hungarian patent document No. 196,979 deserves to be highlighted. According to this method, the compound of formula (I) can be finally prepared through a compound which is assumed to be a ketene imine. This compound was not isolated and its chemical properties were not defined. The reaction was carried out in a very dilute solution (5 g/360 ml of solvent), and a considerable amount (amounting to 50% of the weight of the product obtained) of silver nitrate was used. According to the examples in this patent document, an in situ prepared ketene imine derivative was obtained by treating a methylthionitro derivative with silver nitrate and under the influence of methylamine, which then gave impure ranitidine directly without isolation. The yield of recrystallized ranitidine as calculated for the methylthionitro compound was no higher than 58-73%.

The aim of the present invention is thus to provide a method which can be used to produce the intended ranitidine end product in a high yield and in a simple manner on an industrial scale.

The invention is based on the realization that the intended purpose can be achieved very effectively in a one-step reaction from a new diketenimine compound which has been unknown until now, whereby ranitidine is obtained in almost 100% yield.

It has thus been found during the investigations that the diketenimine derivative of formula (II)

(chemical name 1-{2-[(5-N,N-dimethylaminomethyl-2-furyl)-methyl-thio]-ethyl}-2-{2-[(5-N,N-dimethylaminomethyl-2-furyl) -methyl-thio]-1-ethylamino}-3-nitro-4-nitromethylene-2-azetine; hereafter abbreviated: diketenimine derivative), which is easy to prepare from cysteamine hydrochloride and a furfuryl derivative, can be reacted excellently with methylamine in a defined molar ratio, whereby ranitidine base with an excellent quality is obtained in a simple turnover

ning that occurs at room temperature.

The present invention thus relates to a process for the production of 1-{2-[(5-dimethylaminomethyl-2-furyl)-methylthio]ethyl}-amino-1-methylamino-2-nitroethylene with formula (I) (ranitidine), as well as acid addition salts thereof, which is characterized in that the diketenimine compound of formula (II) is reacted with 40% aqueous methylamine, or methylamine in gaseous form, at a temperature of 20-25 °C, after which, if desired, the base obtained is converted into an acid addition salt thereof.

According to a preferred embodiment of the invention, the diketenimine derivative of formula (II) is reacted with 10 mol of 40% by weight aqueous methylamine. The resulting reaction mixture is clarified, filtered and extracted. The compound of formula (I), i.e. ranitidine, is isolated directly or indirectly from the organic phase.

The most important advantage of the present invention is that the intended compound of formula (I) can be produced in a yield of over 90% by using a very simple technological method. The base thus produced can simply be converted into an acid addition salt thereof.

The invention is illustrated in more detail by means of the following examples.

Example 1

8.5 g (0.015 mol) of the diketenimine derivative with formula (II) is dissolved in 30 ml of water and 41 g (0.5 mol) of 40% aqueous methylamine solution is added at room temperature over 15 minutes. After stirring for 1 hour, the mixture is clarified with 0.5 g of celite and 0.5 g of activated carbon at room temperature for 15 minutes, and then filtered. The filtrate is extracted with 40 ml and then twice with 20 ml of chloroform each time. After drying the combined extract over anhydrous sodium sulfate, the drying agent is filtered off, the solvent is evaporated, and the oily residue is recrystallized from 35 ml of ethyl acetate, whereby 9 g (94%) of 1-{2-[(5-dimethylaminomethyl-2-furyl)methyl -thio]-ethyl}amino-1-methylamino-2-nitroethylene, m.p. : 71-73 °C. This product does not contain contamination that can be identified on a thin layer chromatogram (TLC).

Example 2

The procedure described in example 1 is followed, except that methylamine in gaseous form is introduced slowly into the aqueous solution of the diketenimine derivative at room temperature until the reaction of the diketenimine is complete. (This can be demonstrated by means of thin-layer chromatography using a developing system containing acetone/ethyl acetate/ammonium hydroxide in a ratio of 5:5:1.) In this way, ranitidine is obtained in a yield of 9.1 g (95.5 %), m.p.: 71-73 °C. This product does not contain any TLC detectable contamination.

Example 3

A) The procedure described in Example 1 is followed, except that only 8 g (0.1 mol) of 40% aqueous methylamine is used for the reaction, and the reaction mixture is stirred for 2 hours after addition. Ranitidine is obtained in a yield of 8.9 g (93.4%). B) The wet crystals of the ranitidine base are dissolved in 30 ml of ethanol, and the solution is stirred with 0.5 g of celite and 0.5 g of activated carbon at room temperature for 30 minutes. After filtering off the clarifying agent, the filtrate is acidified to a pH value of 5-6 by adding 30% ethanolic hydrogen chloride solution. After cooling (in a bath at 0 °C) with stirring, the product precipitates. After filtration, the product is washed with 10 ml of ethanol kept below 5 °C. The ethanol used for washing can be used as a medium for the next portion. In this way, 8.05 g (76.1%) of ranitidine hydrochloride are obtained.

Example 4

The method according to example 1 can be carried out in such a way that the oily product obtained after evaporation of chloroform is dissolved in 30 ml of absolute ethanol and the pH value in the solution is adjusted to a value of 5-6 by adding concentrated ethanolic hydrogen chloride solution. After inoculation, the solution is stirred at 5-10 °C for 1 hour. The crystalline precipitate is filtered off, washed with ethanol, cooled to 5 °C and then dried under reduced pressure at room temperature, whereby 9.4 g (89%) of ranitidine hydrochloride is obtained.

Example 5

By carrying out the method according to example 4 on a 1000-fold scale, 950 g (89.9%) of ranitidine hydrochloride are obtained.

Claims (2)

1. Process for the preparation of 1-{2-[(5-dimethyl-aminomethyl-2-furyl)-methylthio]-ethyl}-amino-1-methylamino-2-nitroethylene with formula (I) (ranitidine) as well as acid addition salts thereof, characterized in that the diketenimine derivative of formula (II) is reacted with 40% aqueous methylamine, or methylamine in gaseous form, at a temperature of 20-25 °C, after which, if desired, the base obtained is converted into an acid addition salt thereof. 2. Method according to claim 1, characterized in that 10 mol of 40% by weight aqueous methylamine solution is used in the reaction.