HU196979B - Process for producing basic thioether and salt - Google Patents

Description

The present invention relates to a novel process for the preparation of the compounds of the formula I - [2

- [5- (Dimethylaminomethyl) -2- (furylmethylthio) ethyl]} amino-1- (methylamino) -2-nitro

- ethylene and its hydrochloride.

The compound of formula (I) (internationally generic name: ranitidine) is an excellent gastric and duodenal ulcer drug due to its selective inhibitory action on H-2 receptors. The ranitidine hydrochloride of formula (I) is used in medicine.

The following procedures are described in the literature for the preparation of ranitidine hydrochloride of formula (I).

(a) Example 32 on page 75 of German Patent Application 2734070 discloses that the hydrochloride of compound (I) is prepared by dissolving the base (I) in hydrochloric ethanol and precipitating the hydrochloride from this solution with ethyl acetate. . The yield of the hydrochloride based on the base introduced was 89.6%.

b) Example 8 on page 8 of Belgian Patent No. 890574 'is prepared by adding concentrated hydrochloric acid to an aqueous isopropanolic solution of the base of formula (I) and precipitating the hydrochloride with additional 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 present state of the art, a base of formula (I) of sufficient quality must first be prepared to form the hydrochloride of the compound of formula (I). The preparation of this base is carried out according to Example 24 on page 68 of German Patent Specification No. 2 734 0 / U, cited above, by first using the 2 - [(2-aminoethyl) thio-formula (11). methyl] - 5 - (dimethylaminomethyl) furan is reacted with 1,1 - bis (methylthio) - 2 - nitroethylene (III) in acetonitrile solution at reflux for 14 hours, followed by removal of the solvent. the crude distillation residue is also interacted with methanolic methylamine at reflux. (Hereinafter, this process is referred to as Literature Method A.) The yield is 79.9% as described. One major disadvantage of this description is that it does not characterize the product of the first step of the two-step reaction, while the other deficiency refers to Example 15 on page 61 of the cited application, which does not describe the exact crystallization conditions of the base. is of decisive importance for the yield and quality of the base.

Examining the procedure of Example 24, it was found that, following the procedure described in the Example, the first step was to obtain a highly impure, oily consistency of the compound of Formula (IV), from which the base of Formula (I) it cannot be prepared as described in the example. (In our experiments, the crude product of Formula IV, prepared as described in the above Example, can only be purified and homogenized in a high-loss, time-consuming and laborious manner (e.g., by column chromatography). It is not possible to produce a base of formula (I) corresponding to the above consequences from the compound of formula IV.

Another method for preparing the base of formula (I) is disclosed in U.S. Patent No. 194,849. Hungarian patent specification. In this connection, the compound of formula (IX) is reacted in the presence of a heavy metal salt, such as copper (I) chloride or silver nitrate, with a proton-binding agent of formula (V).

It is converted to 3 - nitro - keteneimine, which is then reacted with a base of formula (II) to form the base of formula (I). For example, the base I is described as being quite low (20% in Example 1 and 58% in 2 in Example 2. [Purification of crude base I is not reported either.) process is hereinafter referred to as the "B" process. Regarding the identity and quality of the product obtained, on the one hand, elemental analysis and NMR spectroscopy are disclosed and, on the other hand, the product obtained is identical to the ranitidine base obtained in Example 15 of German Patent Publication No. 2 734 070. -hydrochloride.

Accordingly, it is an object of the present invention to provide a process for the preparation of the base and its hydrochloride of formula (I) which can be conveniently prepared and commercially available on an industrial scale.

It has now been found that the above object is fully attained if the 1- (2- [5- (dimethylamino) amino) of formula (VI) is

- methyl) -2 - (furylmethylthio) ethyl]} - amino - 1

- 1- (2- (5- (dimethylaminomethyl)) of formula (VII) prepared in situ from (substituted - thio) -2-nitroethylene - wherein R is a C 1-4 alkyl group in a simple manner and in excellent yield; 2 - (furyl - methylthio) ethyl] - 3 - nitro - keteneimine is reacted with methylamine.

This discovery was unexpected for several reasons. Only a simple structure of nitro keteneimine (V), quoted in the literature in connection with process B, is known in the literature and became available very recently. It was not predictable that nitro-keteneimine of formula (VII) with a more complex structure could be formed from a compound of formula (VI) in a very short time (a few minutes) without either starting the compound of formula (VI) or the other compound moiety of the resulting compound of Formula VII not involved in the targeted reaction would be altered; likewise, it was not expected that the compound of formula (VII) would undergo an additive reaction with methylamine in a very short period of time, and this interaction, we observed, resulted in a very pure base of formula (I).

SUMMARY OF THE INVENTION The present invention relates to a novel process for the preparation of 1- (2- / 5- (dimethylaminomethyl) -2-furylmethylthioethyl) amino-1- (methylamino) of formula (I). For the preparation of 2 - nitroethylene and its hydrochloride, which comprises a compound of formula (VI): 1- (2- / 5- (dimethylaminomethyl) -2 - (furylmethylthio) ethyl) -. amino -1 - (substituted - thio) -2-nitroethylene - wherein R is C 1-4 alkyl -

196,979 in a polar organic solvent, optionally in the presence of an acid scavenger, with a salt or oxide of a heavy metal having a specific gravity of at least 6 · 1 (F kg / m ³⁾ , followed by 1- (2- / 5-) (dimethylamino methyl) -2- (furylmethylthio) ethyl] -3-nitro ketene imine is reacted with methylamine and finally the base of formula I obtained is isolated, purified if necessary and / or optionally, if desired, converting it to its hydrochloride.

The compound of formula VII formed as an intermediate in the process of the invention is novel. Formation of this compound is demonstrated chemically and / or spectroscopically.

The in situ formation of the compound of Formula VIII has been chemically demonstrated by reacting the compound of Formula VI with a heavy metal alkyl mercaptide (e.g., silver methyl mercaptide) formed by the reaction of a heavy metal salt (e.g., silver nitrate). ) were filtered and analyzed. Since the formation of the quantitatively formed heavy metal alkyl mercaptide can only be explained by the simultaneous formation of compound (VII), this assay provides indirect chemical evidence for the formation of compound (VII). 1- (2- / 5- (Dimethylaminomethyl) -2- (furylmethylthio) - (VIII) formed in situ by reaction of the compound of formula VI with the heavy metal salt and oxide. ethyl) -3-nitro ketene imine was detected directly in the solution by IR spectroscopy. The absorption typical for the keteneimine bond (C = C = N) occurred at 2160 cm ^-1 .

One of the compounds of formula VI used for the preparation of compound (VII), the compound of formula (IV), is known in the literature (European Patent Application Nos. 2930 and 57981). However, this compound, as well as the novel compounds of formula (VI), may conveniently be prepared using the compound of formula (II) and the compound of formula (VIH) as described in Example 1 of the present invention.

Compounds of formula (Vili) are known from Acta Chem. Scand. 21, 2797 (1967)]; or by known methods. For the preparation of the keteneimine (VII) as the compound (VI), it is preferable to use, for example, the compound (VI). Heavy metal salts having a specific gravity of at least 6 · 10 ³ kg / dm ^{3 are} preferably silver nitrate or copper chloride, and mercury (II) oxide is preferably used as its oxide. For example, organic bases may be used as acid scavengers. Formation of compound (VIII) and its reaction with methylamine are conveniently carried out at room temperature or slightly below. Polar organic solvents as solvents, even some low molecular weight! an aliphatic alcohol such as ethanol may be used.

In a preferred embodiment of the invention, a solution or suspension of the compound of formula IV in anhydrous ethanol is treated with silver nitrate dissolved in anhydrous ethanol at 5 to 30 ° C, followed by precipitation of the immediately formed silver methyl mercaptide precipitate. After the addition of methylamine, the reaction mixture is filtered and the solvent is removed from the filtrate. The residue, which consists essentially of the base of formula I, i.e. ranitidine, in addition to the corresponding salt of methylamine, is worked up in the usual manner. The ranitidine thus obtained is optionally recrystallized and optionally converted to its hydrochloride.

In a further preferred embodiment, an ethanolic methylamine solution containing silver nitrate is added dropwise to an ethanol suspension of the compound of formula (IV), as follows.

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

Both reaction steps of the process of the invention, i.e. the formation of the compound of formula (VIII) and its reaction with methylamine, are carried out very quickly at room temperature or slightly lower. One consequence of this is that the compound of formula (VII) will not decompose and that its degradation products will not contaminate the resulting base of formula (1); the other consequence is energy savings and, due to the short turnaround time, the device fleet can be effectively utilized.

The very rapid progress of the reaction is best achieved by the fact that the methylamine, which is normally gaseous, can be used in any excess and can be easily removed without the need for heat. In contrast to this, the base of formula (I) is prepared by the above-mentioned literature process "B", that is, by converting a compound of formula (IX) to a nitro keteneimine of formula (V), which is added reaction with the base II, the base II can only be used in stoichiometric amounts, so it cannot be accelerated by the addition of the base II because this base is fragile, heat sensitive only at high temperature and very good vacuum it can be removed, partial decomposition during distillation is avoided, and the decomposition products of either the remainder of the base or the removal of excess by distillation seriously contaminate the base of formula (1) formed.

Contrary to the literature process "A", in which each mole of methylmercaptan is liberated in each step, the process of the invention traps this toxic gas in the form of a harmless, non-volatile heavy metal alkylmercaptide and thus does not pollute the environment.

The yield of the base of formula (I) obtained by the process according to the invention in relation to compound (11), which is also the starting material of process B, is about 73% and can be used to form a hydrochloride salt of pharmaceutical quality. The hydrochloride of the quality thus obtained does not require further purification. In contrast, the yield of the commercial process B for compound 11 is only 58% and the base I obtained is not directly suitable for the preparation of ranitidine hydrochloride of sufficient purity.

Accordingly, the process of the invention is suitable for the base and its hydrochloride of formula (I)

196,979 for simple, high yield production, even in industrial scale.

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

Example 7

1- (2- (5- (Dimethylaminomethyl) -2- (furyl

Preparation of the base of methylthio) ethyl]} amino - 1 - (methylamino) 2 - nitroethylene [(]) and its hydrochloride.

99.5 g (0.30 mol) of 1- (2- (5- (dimethylaminomethyl) -2- (furylmethylthio) ethyl]} amino-1 (methylthio) -2 To a suspension of nitroethylene (IV) in ethanol (2500 ml) was added a solution of silver nitrate (51.0 g, 0.30 mol) in absolute ethanol (4000 ml) with stirring at 10 ° C for 1 minute. After stirring for a few minutes, 557 ml of a 29.3% solution of methylamine in ethanol are added and the reaction mixture is stirred for 2 hours at room temperature. The precipitate, which is composed of silver methylmercaptide, is filtered off and the filtrate is filtered off. The residue is taken up in 600 ml of water and the pH is adjusted to 5.5 with 1 N hydrochloric acid, extracted twice with 600 ml of ethyl acetate and the pH of the aqueous phase is increased with 1 N sodium hydroxide solution.

It was adjusted to 10 and extracted with ethyl acetate (6 x 1200 mL). The organic phases from the latter extracts were combined, dried and evaporated in vacuo. This gave 79 g (84%) of crude ranittin base.

To prepare the hydrochloride salt, the crude ranitidine base was dissolved in 380 mL of abs. dissolved in ethanol and the pH of the solution is adjusted to 5.5 with concentrated aqueous hydrochloric acid at 0 to 5 ° C with stirring. Stirring is continued at 0 'C for 40 minutes and then allowed to stand at 0-5 C overnight.

The crystalline precipitate was filtered off, washed with ethanol and dried. 57.45 g (54.6%) of the title hydrochloride salt are obtained. Mp: 143 'C. Further evaporation and crystallization of the mother liquor gave 23.15 g (22%) of the hydrochloride salt. Mp: 143 'C.

In this example, 1- (2- (5- (dimethylaminomethyl) -2-furylmethylthio) ethyl]} amino-1- (methylthio) of formula (IV) used as starting material was used as starting material.

Preferably, 2-nitroethylene can be prepared as follows.

To a solution of 52.80 g (0.32 mol) of 1,1-bis (methylthio) -2-nitroethylene in 238 ml of toluene at 80 ° C was added 17.12 g (0.008 mol) of 2 - ((2-amino) - ethyl)

thiomethyl] - 5 - (dimethylaminomethyl) furan was added and the resulting mixture was stirred at this temperature for 70 minutes. It is then cooled to 3-4 ° C and the excess dithioester precipitated is isolated by filtration. Weight - 23.9 g (m.p. 121-124 'C). The toluene filtrate was extracted with 120 mL of 1N hydrochloric acid and then with 80 mL of water, and the combined aqueous layers were washed with toluene. (Evaporation of the toluene phase gives an additional 7.05 g of dithioester.) The pH of the aqueous phase is adjusted to 8 and three times

Extract with ethyl acetate (120 mL). The organic phases from the latter extractions were combined, dried and evaporated under reduced pressure. In this way, 22.87 g (86.3%) of the compound of formula IV are obtained, which is sufficiently pure for the reaction according to the example. M.p. 68-69 'C.

Example 2

1-12- (5- (Dimethylaminomethyl) -2- (furyl

- Methylthio) ethyl]] - amino - 1- (methylamino) 2 - nitroethylene [base (I)] and its hydrochloride g (0.015 mol) 1- (2- (5- (dimethyl)) - a suspension of - amino methyl) -2 - (furylmethylthio) ethyl]} - amino - 1 - methylthio - 2 - nitroethylene (compound of formula IV) in 125 ml of absolute ethanol with stirring, At 6 'C for one minute,

2.55 g (0.015 mol) of silver nitrate in 200 ml of abs. ethanol solution was added, the mixture was stirred for an additional 3 minutes at 5 ° C, and then 30 ml of a 27% solution of methylamine in ethanol was added. The mixture was stirred at room temperature for 2 hours and then filtered. The filtrate was allowed to stand at 5 ° C for one day, filtered again, the gray was concentrated in vacuo at room temperature, water (50 mL) was added and the pH was adjusted to 5.5 with 1 N hydrochloric acid. It was then extracted with dichloromethane (2 x 70 mL), then the pH of the aqueous phase was adjusted to 10 with 1N sodium hydroxide solution and extracted with dichloromethane (4 x 70 mL). The organic phases from the latter extractions were combined, dried, evaporated and four volumes of ethyl acetate were added to the residue. The precipitated crystals are filtered off and dried. 2.75 g (58.0%) of the title base are obtained, m.p. 66-68 'C. Repeated evaporation and crystallization of the mother liquor afforded an additional 0.55 g (11.2%) of the title base.

Example 3

1- (2- (5- (Dimethylaminomethyl) -2- (furyl

- methylthio) ethyl]} - amino - 1 - (methylamino) 2 - nitroethylene (base of formula (1))

1.66 g (0.005 mol) of 1- (2- (5- (dimethylamino)

(methyl) -2 - (furylmethylthio) ethyl]) - amino - 1

- (methylthio) -2-nitroethylene 10 ml abs. A solution of silver nitrate (0.85 g, 0.005 mol) in methyl methamine (27% in ethanol) (0.85 g, 0.005 mol) was added with stirring at room temperature. The reaction mixture was stirred for an additional 30 minutes at room temperature, then filtered and the filtrate was concentrated in vacuo. Further, Example 2 gave 1.21 g of the title base. Yield: 77.1%, m.p. 68-70 ° C.

Example 4

1- (2- (5- (Dimethylaminomethyl) -2- (furyl

- methylthio) ethyl]] - amino - 1 - (methylamino) 2 - nitroethylene (base of formula 1)

196,979

1.66 g (0.005 mol) of 1- {2- [5- (dimethylamino)

(methyl) -2 - (furylmethylthio) ethyl]) - amino - 1

To a suspension of (methylthio) -2-nitroethylene in 20 ml of allyl alcohol was added 0.85 g (0.005 mole) of silver nitrate (60 ml) in stirring over 2 to 3 minutes at 8-10 ° C. alcohol solution. At the above temperature, 8 ml of a 27% solution of methylamine in ethanol was added over 1-2 minutes, and stirring was continued at room temperature for 2 hours. The reaction mixture was worked up as in Example 2 to give 0.95 g of the title base. Yield: 60.5%, m.p. 70-72'C.

Example 5

1- (2- (5- (Dimethylaminomethyl) -2-furylmethylthio) ethyl] amino-1- (methylamino) 2-nitroethylene [Base of Formula I )

1.0 g (0.003 mol) of 1- (2- (5- (dimethylaminomethyl) -2- (furylmethylthio) ethyl]) amino-1 (methylthio) -2-nitro- To a solution of ethylene (IV) in ethyl alcohol (5 mL) was added triethylamine (0.3 g, 0.003 mol) and silver nitrate (0.85 g, 0.003 mol) in ethyl acetate (50 mL) was stirred for 1-2 minutes. Then, 5 ml of a 30% ethanol solution of methylamine in ethanol was added dropwise over 1-2 minutes to the precipitated solution, followed by the same procedure as in Example 2. The crude product was subjected to silica gel column chromatography. Yield 0.31 g (30%), mp 66-68 ° C.

Example 6

1- (2- (5- (Dimethylaminomethyl) -2- (furyl

- methylthio) ethyl]} - amino - 1 - (methylamino) 2 - nitroethylene (base 1) in an aqueous suspension of 0.013 mol of freshly prepared Hg (II) oxide with vigorous stirring 2.32 g (0.007 mol). 1- (2- (5

A solution of (dimethylaminomethyl) -2- (furylmethylthio) ethyl] amino-1- (methylthio) -2-nitroethylene in 40 ml of dichloromethane was added. Methylamine gas was then added to the reaction mixture under vigorous stirring at room temperature. (Endpoint of the reaction was monitored by TLC. Adsorption: Kieselgel 60 HF _{2 + 4 + 366} (Reanal, Budapest), Developed with ethyl acetate: acetone 25% aqueous ammonium hydroxide (5: 5: 1)). After completion of the reaction, the reaction mixture is filtered and the filtrate is separated. The organic phase is evaporated and the crude product is chromatographed on a silica gel column. Yield: 0.48 g (22%) of the title compound. Mp: 66-68 ° C.

Example 7

In order to show that the method of the invention, the 1 - (2 - [5 - (dimethyl - amino - methyl ₁₀ methyl) - 2 - (furyl - methyl - thio) - ethyl]} - amino - 1 (methyl - thio) - 2 - nitroethylene (compound of formula IV) first reacts with silver nitrate to form 1- (2- [5] - (dimethylaminomethyl) -2 - (furylmethylthio) ( ₁₅ ) ethyl] -3-nitro-ketene-imine (Compound VII) was reacted with methylamine and the following control experiment was performed.

All were carried out in the same manner as in Example 2, but after the addition of silver nitrate, the precipitate formed in the solution was filtered off, analyzed after washing and drying. Weight of precipitate: 2.28 g (98.1%).

Is the elemental formula calculated for CH ₃ AgS (M = 154.98)? _r analysis values. Ag 69.6, C 7.75.11 1.95%; found values; Ag 69.1, C 7.69, H 1.36%.

Claims

Claims (3)

A process for the preparation of 1- (2- (5- (dimethylaminomethyl) -2- (furylmethylthio) ethyl)} amino-1- (methylamino) -2-nitro- ethylene and its hydrochloride, 35 that 1- (2- (5- (dimethylaminomethyl) -2- (furylmethylthio) ethyl) of formula IV) - amino-1- (substituted-thio) -2-nitroethylene, where R is a C 1-4 alkyl group, in a polar organic solvent, optionally in the presence of an acid scavenger, having a specific gravity of at least 6 10 ³ kg / m ^{3 J} reacting with a salt or oxide of a heavy metal, then reacting the 1-2 - (5 - (Dimethylaminomethyl) -2 - (furylmethylthio) ethyl] -3 - nitro - keteneimine mimethyl ^{45 is} finally contacted and the base (I) obtained is isolated if desired, purified. and / or, if desired, converting it to its hydrochloride in a known manner. 2. The process of claim 1 wherein the heavy metal salt is silver nitrate. 3. The method of claim 1 or 2, wherein said organic solvent is an ₅ 5 low molecular weight aliphatic alcohol.