GB2169600A

GB2169600A - Process for preparing a basic thioether and the salt thereof

Info

Publication number: GB2169600A
Application number: GB08600530A
Authority: GB
Inventors: Dr Endre Kasztreiner; Dr Peter Matyus; Dr Lajos Toldy; Tibor Somogyi; Eszter Diesler; Dr Gyula Horvath; Dr Eva Koczka; Dr Ferenc Szederkenyi; Dora Bobak; Dr Nandor Makk; Dr Tibor Lang; Dr Bela Stefko; Dr Tibor Balogh; Dr Emilia Uskert; Arpad Lazar
Original assignee: Richter Gedeon Vegyeszeti Gyar RT
Current assignee: Richter Gedeon Vegyeszeti Gyar Nyrt
Priority date: 1985-01-11
Filing date: 1986-01-10
Publication date: 1986-07-16
Also published as: ES8703864A1; FI860123A0; GR860058B; AT391470B; GB8600530D0; IT1203727B; FI860123A; ES550809A0; KR860005802A; CS261232B2; HU196979B; DK10486D0; IT8647517A0; HUT38922A; PT81824B; SU1419519A3; FI90419B; ATA3486A; KR920010926B1; NO860071L

Abstract

1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methyl amino-2 - nitroethylene of the formula (I> <IMAGE> and its hydrochloride, are prepared by reacting an 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-(subst ituted thio)-2- nitroethylene of the formula (VI), <IMAGE> wherein R represents an optionally substituted C1-4 alkyl group or an oxoalkyl, aryl, aralkyl, or oxoaralkyl group, with an agent capable of splitting off a mercapten, in an organic solvent, optionally in the presence of an acid-binding agent, then reacting the in situ prepared 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-3-nitroketenei mine of the formula (VII> <IMAGE> with methylamine and finally, if desired, separating the obtained base of formula (I), purifying it and/or, if desired, transforming it to its hydrochloric salt.

Description

SPECIFICATION Process for preparing a basic thioether and the salt thereof This invention relates to a process for preparing thioethers and salts thereof. More particularly it relates to a process for preparing 1 -{2-[5-dimethylaminomethyi -2-(fu ryl methylthio)-ethyl]}-amino-1 -methylamino2-nitroethylene of the formula (I)

and the hydrochloride salt thereof.

The compound of formula (I) (generic name: ranitidine) is a selective histamine H-2 receptor antagonist and, as such, is an outstanding drug for the treatment of gastric and duodenal ulcers. The hydrochloride salt of the compound of formula (I) is used for therapeutical purposes.

The following processes for preparing the hydrochloride salt of the compound of formula (I) are described in the literature: a) According to Example 32 (page 75) in the published German patent application No. 2,734,070, the hydrochloride salt of the compound of formula (I) is prepared by dissolving the base of formula (I) in ethanol-HCL and precipitating the hydrochloride salt formed by adding ethyl acetate to give a 89.6% yield of the hydrochloride salt as calculated for the base used as starting material.

b) According to Example 1 (page 8) of the Belgian patent specification No. 890,574, the hydrochloride salt of the compound of formula (I) is prepared by adding concentrated hydrochloric acid to an aqueous solution of the base of formula I and precipitating the hydrochloride salt formed by adding a further amount of isopropanol to give a 93.9% yield of the hydrochloride as calculated for the base.

Since, the starting material for both of the processes known at present is the base of formula (I), this must first be prepared in an appropriate quality for the subsequent conversion to the hydrochloride salt.

According to Example 24 (page 68) of the above-cited published German patent application No.

2,734,070, this base is prepared by reacting 2-[(2-aminoethyl)-thiomethyl]-5-dimethyl-aminomethylfuran of the formula (II)

with l,l-bis(methylthio)-2-nitroethylene of the formula (III)

in acetonitrile solution at the reflux temperature for 14 hours, then removing the solvent and boiling the crude distillation residue under reflux with a methanolic solution. (Hereinafter, this process is referred to as literature process 'A'). According to the description, the yield is 79.9%. A considerable deficiency of this decription lies in the fact that the product of the first step of the two-step reaction is not characterized.Another deficiency of this prior art is that the exact conditions for the recrystallization of the final product, Example 15 (page 61) of the published patent application, are not given, even though they are of decisive importance to both the yield and the quality of the base of formula (I) obtained.

It was found that, by following the process described in Example 24 of this published German application, a very impure oily product was formed in the first step which could be characterized by the formula (IV)

However, the base of formula (I) could not be obtained in a quality suitable for the preparation of its hydrochloride salt in the way described in the Example. [According to our experiments, the crude product of formula (IV) prepared in this manner could only be purified and made homogeneous, with high losses, by a tedious and complicated procedure (e.g. by column chromatography separation)J. Subsequently, it has been found that, by using the process described in Example 24, a base of the formula (I) with a quality satisfying the above requirements could not be prepared even from a purified compound of the formula (IV).

Another process for the preparation of the base of formula (I) is reported in Hungarian patent application No. 1827/83 published under No. T/31115, according to which the compound of formula (IX)

is transformed to 1-methyl-3-nitroketeneimine of the formula (V) O,I\I-CH=C=N-CH (V) by using a heavy metal salt, e.g. silver nitrate or cuprous chloride, in the presence of a proton-binding agent, and the keteneimine of formula (V) is brought into an addition reaction with the base of formula (II) to give the base of formula (I).The aforementioned patent application contains two Examples, neither of which can, however, be evaluated as the yields are not mentioned. [The purification process of the crude base of formula (I) is also not reported Hereinafter, this process is referred to as literature process 'B'. Spectroscopical proofs of the identity and quality of the product obtained, are quoted but are not described. However, the product obtained is stated to be identical with the ranitidine base prepared as described in Example 15 of the published German patent application No. 2,734,070. Unfortunately, our own investigations showed that this latter base is not suitable to prepare ranitidine hydrochloride of satisfactory purity.

The aim of the present invention is to provide a simple process for the preparation of the base of formula (I) and of its hydrochloride salt in a good yield and at an industrial scale.

We have found that this aim can be substantially achieved when a 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-(substituted thio)-2-nitroethylene of the general formula (VI),

wherein R represents an optionally substituted alkyl oxoalkyl group or an aryl, aralkyl or oxoaralkyl group, is transformed in situ into a 1[2-[5-dimethyIaminomethyl-2-(furyImethyIthio)-eThylJ}-3-nitrnketeneimine of the formula (VII)

in a simple way and in an excellent yield and then the keteneimine of the formula (VII) is reacted with methylamine to form the compound of formula I.

This discovery is surprising for a number of reasons. The simple nitroketeneimine of formula (V) cited in connection with literature process 'B' has only recently become known. It was not foreseeable that the rather complicated structure of the nitroketeneimine of formula (VII) could be formed from a compound of general formula (VI) within an extraordinarily short time (i.e. within a few minutes) without any alteration of the molecular moieties not participating in the aimed reaction of either the starting compound of the general formula (VI) or the formed product of formula (VII). Similarly it could not be expected that the complicated structure of the nitroketeneimine of formula (VII) would show a very rapid addition reaction with methylamine to give a base of formula (I) of very high purity and, according to our observations, almost without any side reactions.

Thus, the present invention relates to a process for preparing 1-{2-[5-dimethylaminomethyl-2-(furylme thylthio)-ethyl]}-amino-1-methylamino-2-nitro ethylene and its hydrochloride salt, which comprises reacting a 142-[5-dimethylaminomethyl)-2-(furyl methylthio)-ethyl]}-amino-1-(su bstituted thio)-2-nitroethylene of the general formula (VI), wherein R stands for an optionally substituted alkyl group containing 1 to 4 carbon atoms or an oxoalkyl, aryl, aralkyl or oxoaralkyl group, with an agent serving to eliminate a mercaptan, in an organic solvent, optionally in the presence of an acid-binding agent, then reacting the 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-3-nitroketeneimine of the formula (VII) prepared in situ with methylamine followed, if desired, by separating the obtained base of formula (I), and, if desired, purifying it and/or transforming it to its hydrochloride salt.

The compound of the formula (ill) formed as an intermediate in the process of the invention is new. The formation of this compound has been supported by the fact that on the interaction of 1-{2-[5-dimeth ylamino-methyl-2-(furylmethylthio)-ethyl]}-amino-1 -methylthio-2-nitroethylene [compound of the formula (IV)] with silver nitrate, silver methylmercaptide was obtained in a nearly quantitative yield, as is described below.

One of the compounds of general formula (Vl) used for preparing the compound of formula (VII), namely the compound of formula (IV), can be considered to be a known substance on the basis of comparison of the general formula reported in the process variant b) of claim 37 (page 7) of the published German patent application No. 2,734,070 with Example 24 (page 68), although no characteristics or the chemical name of this substance are given. No other compound of formula (VI) is mentioned in this patent application. According to Example 1 of the published European patent application No. 0,002,930, the compound of formula (IV) melts at 71nC. To the best of our knowledge, no other compound of the formula (VI) has been described in the literature. Thus, the compounds of general formula (VI) are new, except the compound of formula (IV).These compounds may be prepared in known manner by reacting the base of formula (II) with a compound of the formula (VIII),

where R is as hereinbefore defined.

Some of the compounds of general formula (VIII) are known [Acta Chem, Scand. 21, 2797 (1967); Chem. Ber. 100,591(1967)]. The new compounds of the general formula (VIII) can be prepared in a known way.

As a compound of general formula (VI), the compound of formula (IV) is useful e.g. for preparing the nitroketeneimine of formula (VII). Metal preferably heavy metal salts, such as, for example, silver nitrate or cuprous chloride, metal oxides or finely distributed metals are desirably employed as the agents for eliminating the mercaptan. Organic bases are suitable acid-binding agents. Both the formation of the compound of formula (VII) and its reaction with methylamine are preferably carried out at a temperature equal to or somewhat lower than room temperature. Organic solvents such as lower aliphatic alcohols, e.g. ethanol, may suitably be used.

A preferred embodiment of the invention comprises treating a solution or suspension of the compound of formula (IV) in absolute ethanol with silver nitrate at 5 to 30"C and adding methylamine after the precipitation of the directly formed silver mercaptide, then filtering the reaction mixture, removing the solvent from the filtrate and working up the residue in the usual way. The residue comprises the base of formula (I) in addition to the appropriate salt of methylamine. If desired, the thus-obtained ranitidine is recrystallized and, if desired, it is transformed to its hydrochloride.

Another preferred embodiment of the invention comprises adding an ethanolic methylamine solution containing silver nitrate dropwise to an ethanolic suspension of the compound of formula (IV) and then following the process described above.

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

- Both steps of the process of the invention, i.e. the formation of the compound of formula (VII) and its reaction with methylamine proceed rapidly at a temperature equal to or somewhat lower than room temperature. This prevents the decomposition of the compound of formula (VII) and thus the base of formula (I) formed will not be contaminated by decomposition products. As a consequence of the short processing time (production period), the pool of equipment can be efficiently utilized and energy can be saved.

The rapid reaction is largely due to the fact that methylamine, being gaseous under normal conditions, can be used in an optional excess and after the reaction this excess can be easily removed without any heat demand. In a sharp contrast thereto, when the base of formula (I) is prepared by using the abovecited literature 'B' process, i.e. by transforming the compound of formula (IX) to the nitroketeneimine of formula (V) and by bringing the latter compound to an addition reaction with the base of formula (II), then the base of formula (II) can only be used in a stoichiometric amount and thus the addition reaction cannot be accelerated by using an excess of the base of formula (II). This base is unstable and sensitive to heat but since it can only be removed under high vacuum and temperature, a partial decomposition of the base cannot be avoided during distillation. Thus, the obtained base of formula (I) becomes severely contarninated either by the remaining base or by the decomposition products arising from the distillation of the excess base of formula (II).

In contrast to the literature process 'A', wherein one mole of methyl mercaptan is liberated in each step, in the process of the invention this toxic gas is bound in the form of a harmless, non-volatile metal mercaptide and thus the environment is not polluted.

The yield of the crude base of formula (I) obtained by using the process of the invention is nearly quantitative. This crude product contains only a very little amount of contamination (except the salt of the acid-binding agent used). By using a simple purifying process, a completely homogeneous base of the formula (I), which is useful in forming the hydrochloride salt, is obtained in a very good yield (about 75%). The thus-obtained hydrochloride salt does not need any further purification.

Based on these facts, the process of the invention is useful for the simple preparation of the base of formula (I) and its hydrochloride in a good yield and at an industrial scale.

The process of the invention is illustrated in detail by the following non-limiting Examples.

Example 1 Preparation of 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methylamino-2-nitroe- thylene [base of the formula (1)]. 51.0 g (0.30 mole) of silver nitrate dissolved in 4000 ml of absolute ethanol are added to a solution containing 99.5 g (0.30 mole) of 142-[5-dimethylamino-methyl-2-(furylme- thyithio)-ethyl]3-amino-1-methylthio-2-nitroethylene [compound of the formula (IV)] in 2500 ml of absolute ethanol at 10"C within one minute to immediately form silver methylmercaptide. Then 557 ml of a 29.2% ethanolic methylamine solution are added and the mixture is stirred at room temperature for 2 hours.

The precipitate (which is silver methylmercaptide in a yield of 98.1% according to its weight and composition) is filtered and the filtrate is evaporated to dryness at room temperature. The evaporation residue is taken up in 600 ml of water and extracted eight times with 1200 ml of ethyl acetate each while adjusting the pH value to 10, if needed. The organic phases are combined, dried and evaporated under reduced pressure. The crude ranitidine is obtained as an evaporation residue in a yield of 79 g (84%).

For the preparation of the hydrochloride, the crude ranitidine base is dissolved in 380 ml of absolute ethanol and the pH value of the solution is adjusted to 5.5 by adding concentrated aqueous hydrochloric acid at 0 to 5"C. The mixture is stirred at 0 C for 40 minutes.

The crystalline precipitate is filtered out, washed with ethanol and dried to give ranitidine hydrochloride in a yield of 57.45 g (54.6%), m.p.: 143"C. A second crop of 23.15 g (22.0%) is obtained from the mother liquor, m.p. 143"C.

1 2-[5-Dimethylaminomethyl-2-(furylmethylthio)-ethylj}-amino-1 -methylthio)-2-nitroethylene [compound of the formula (IV)] used as starting material can be prepared according to the prior art e.g. Example 1 of the published European patent application No. 0,002,930.

Example 2 Preparation of 1 -{2-[5-dimethylaminomethyl-2-(furyl methylthio)-ethylj}-amino-1 -methylamino-2-nitroe- thylene [base of the formula (I)] and its hydrochloride.

A solution containing 2.55 g (0.015 mole) of silver nitrate in 200 ml of absolute ethanol is added to a solution containing 5 g (0.015 mole) of 12-[5-dimethylaminomethyl-2Afurylmethylthio)-ethylj}-amino-1- methylthio-2-nitroethylene [compound of formula (IV)] in 125 ml of absolute ethanol within one minute while stirring at 6"C to immediately form silver methylmercaptide. The mixture is stirred at 5"C for an additional 3 minutes, then 30 ml of a 27% ethanolic methylamine solution are added. The mixture is stirred at room temperature for 2 hours and then filtered. The filtrate is set aside at 50C overnight, filtered again and the filtrate is evaporated at room temperature under reduced pressure.After adding 50 ml of water to the residue, the pH value is adjusted to 5.5 by adding 1 N aqueous hydrochloric acid. The mixture is extracted twice with 70 ml of dichloromethane each, then the pH value of the aqueous phase is adjusted to 10 by adding 1 N sodium hydroxide solution and extracted four more times with 70 ml of dichloromethane each. The organic phases obtained from the latter extractions are combined, dried, evaporated and four volumes of ethyl acetate are added to the evaporation residue. The precipitated crystals are filtered and dried to give 3.02 g (64.0%) of the aimed base, m.p.: 68-70"C. After repeated evaporation of the mother liquor and recrystallization of the residue, an additional amount of 0.55 g (11.2%), of the aimed base is obtained.

The base prepared according to Example 2 may be transformed to its hydrochloride e.g. as follows.

3.5 g of crude ranitidine are dissolved in 17.5 ml of absolute ethanol and the pH value of this solution is adjusted to 5 to 5.5 by adding concentrated aqueous hydrochloric acid at 0 C while stirring. The mixture is stirred at 0 C for an additional 40 minutes and then set aside at 0 to 5 C overnight. The crystalline precipitate is filtered, washed with ethanol and dried to give 3.72 g (84.4%) of the aimed hydrochloride, m.p.: 143"C.

Example 3 Preparation of 142-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1-methylamino-2-nitroe- thylene [base of the formula (I)].

A solution prepared from 0.85 g (0.005 mole) of silver nitrate with 10 ml of a 27% ethanolic methylamine solution is added to 1.66g (0.005 mole) of 142-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}- amino-1-methylthio-2-nitroethylene [compound of the formula (IV)] suspended in 10 ml of absolute ethanol at room temperature while stirring. The mixture is stirred at room temperature for an additional 30 minutes, then filtered and evaporated under reduced pressure. The working-up is carried out as described in Example 2 to give 1.21 g (77.1%) of the aimed base, m.p. 68-70"C.

Example 4 Preparation of 1-C2-[5-di ethyl 1 -{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-amino-1 -methylamino-2-nitroe- thylene [base of the formula (I)].

A solution containing 0.859 (0.005 mole) of silver nitrate in 60 ml of allyl alcohol is portionwise added to a solution containing 1.66 g (0.005 mole) of 1-[2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethylj:rb- amino-1-methylthio-2-nitroethylene [compound of the formula (lV)j in 20 ml of allyl alcohol within 2 to 3 minutes at 8 to 10 C while stirring. Then 8 ml of a 27% ethanolic methylamine solution are added at the same temperature within 1 to 2 minutes and the mixture is stirred at room temperature for 2 hours. The working-up is carried out as described in Example 2 to give 0.95 g (60.5%) of the aimed base, m.p.: 70 72 C.

Example 5 Control experiment The following control experiment was carried out in order to support that, in the process of the invention, 1 -{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethylj}-amino-1 -methylthio-2-nitroethylene [compound of the formula (IV)] reacts first with silver nitrate and then, simultaneously with the precipitation of silver methylmercaptide, the th us-formed 1 -(2-[5-di methylaminomethyl-2-(f uryl methylthio)-ethyl])-3-n itro- keteneimine [compound of the formula (Vll)] reacts with methylamine.

The process described in Example 1 was followed, except that, after adding the silver nitrate, the precipitate formed in the solution was filtered, washed, dried and analyzed. The precipitate weighed 2.28 g (98.1%) Analysis for CH3AgS (molecular weight 154.98) Calculated: C 7.75%; H 1.95%: Ag 69.6%.

Found: C 7.69%; H 1.36%; Ag 69.1%.

Claims

1. A process for the preparation of 1 -{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethylj}-amino-1 - methylamino-2-nitroethylene of the formula (I)

and its hydrochloride, which comprises reacting a 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)- ethyl])-amino-l-(substituted thio)-2-nitroethylene of the general formula (VI),

wherein R represents an optionally substituted alkyl group containing 1 to 4 carbon atoms or an oxoalkyl, aryl, aralkyl or oxoaralkyl group, with an agent serving to eliminate a mercaptan, in an organic solvent, optionally in the presence of an acid-binding agent, then reacting the in situ prepared 1-{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-3-nitroketeneimine of the formula (VII)

with methylamine followed, if desired, by separating the obtained base of formula (I), and, if desired, purifying it and/or transforming it into its hydrochloride salt.

2. A process as claimed in claim 1, which comprises using silver nitrate as an agent serving to eliminate methylmercaptan from a compound of formula (VI) in which R is a methyl group.

3. A process as claimed in claim 1 or claim 2, which comprises using a lower aliphatic alcohol as an organic solvent.

4. 1 -{2-[5-dimethylaminomethyl-2-(furylmethylthio)-ethyl]}-3-nitroketeneimine of the formula (VII)

5. Compounds of general formula (VI)

wherein R represents an optionally substituted alkyl or oxoalkyl group or an aryl, aralkyl or oxoaralkyl group with the proviso that R may not represent a methyl group.

6. A process as claimed in claim 1 substantially as hereinbefore described.

7. A process for the preparation of a compound of formula (I) as defined in claim 1 substantially as hereinbefore described and with reference to the Examples.

8. Each and every novel product, process or intermediate hereinbefore described.