FI90419B - Process for the preparation of 1- 2- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl] amino-1-methylamino-2-nitroethylene and its hydrochloride - Google Patents

Description

90419

The present invention relates to a new process for the preparation of 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl]} amino-1-methylamino-2-nitroethene and its hydrochloride.

Η3 ° \ i — I

N_H2C CH2 "S" (CH2} 2 "NH" jf "nh_ch3 (1> H3C CH-NO2 according to 1-12- [5-dimethylaminomethyl-2- (furylmethyl) ethyl] ethyl) -amino-1-methylamino-2-nitroethylene and its hydrochloride.

Because the compound of formula (I) (common name: ranitidine) is a selective histamine H-2 receptor antagonist, it is an excellent drug against gastric and duodenal ulcers. For therapeutic purposes, the hydrochloride of the compound of formula (I) is used.

The following methods for the preparation of the hydrochloride of the compound of formula (I) have been described in the literature: a) According to Example 32 ** · ': (p. 75) in DE application 2,734,070, the hydrochloride of the compound of formula (I) is prepared by dissolving base in ethanol and precipitating the hydrochloride formed by adding ethyl acetate to give the hydrochloride in 89.6% yield based on the base used as starting material.

b) According to Example 1 (p. 8) of BE 890,574, the hydrochloride of the compound of formula (I) is prepared by adding concentrated aqueous hydrochloric acid to the solution and precipitating the formed hydrochloride by adding further isopropanol to give the hydrochloride in 93.9% yield based on base. .

/ - The starting material for both methods is thus a base of formula (I). Therefore, based on currently known methods, the base of formula (I) should first be prepared in a suitable quality for the formation of the hydrochloride. According to Example 24 (p. 68) of the above German patent application 2,734,070, this base is prepared by first introducing H3 < 2 - [(2-aminoethyl) -thiomethyl] -5-dimethylaminomethylfuran according to H3C to react 1,1-bis (methylthio) -2 according to formula (III) / s-ch3 O2N-CH = C (III) s-ch3 with nitroethylene in acetone-nitrile solution at reflux for 14 hours, after which the solvent is removed and the crude distillation residue is refluxed in methanol-containing solution. (Hereinafter, this method is called the literature method "A"). According to the explanation, the yield is 79.9%. A significant shortcoming of this explanation is the fact that the product of the first step of this two-step reaction has not been characterized. Another disadvantage is that the final product is mentioned in Example 15 of the above patent application (p. 61), which, however, does not state the exact conditions for recrystallization, although they are crucial both for the yield and quality of the base of formula (I).

Examining the process described in Example 24 of this DE patent application, it was found that following this process in the first step a very impure oily product is formed which can be characterized by the formula (IV) 3 90419 h3c YH2cJ ^ LcH2-S- (CH2) 2-NH-CS-CH3 ( IV) H 3 CO 0 CH-NO 2 but from which it was not possible to obtain a base of formula (I) as described in the example in a quality suitable for the preparation of the base hydrochloride of formula (I).

[According to our studies, the crude product of formula (IV) prepared by the method described in the above example could be purified and homogeneous only with high losses in a time-consuming and complex manner (e.g., column chromatography separation) J. It has further been found that using the method set forth in Example 24, a base of formula (I) whose quality meets the above requirements could not be prepared even from a pure compound of formula (IV).

HU patent application 1827/83, published under number T / 31115, discloses another process for the preparation of a base of formula (I) according to which a compound of formula (IX) / S-CH 3 O 2 N-CH = C (IX) NH-CH 3 the compound is converted to the 1-methyl-3-nitroketenimine of formula (V) O 2 -CH = C = N-CH 3 (V) using a heavy metal salt, e.g. silver nitrate or copper chloride in the presence of a proton scavenger and a ketene of formula (V) the imine is subjected to an addition reaction with a base of formula (II) to form a base of formula (I). This patent application contains two examples, neither of which, however, can be evaluated because the yield is 4,90419 and is not mentioned. [A method for purifying the crude base of formula (I) is also not shown.] Hereinafter, this method is referred to as literature method "B". As for the identity and quality of the product obtained, spectroscopic experiments have been mentioned, but have not been explained. On the other hand, the product obtained is shown to be identical to the ranitidine base prepared as described in Example 15 of DE-Application 2,734,070. However, according to our own studies, the latter base is not suitable for the preparation of ranitidine hydrochloride in satisfactory purity.

It is therefore an object of the present invention to provide a process for the preparation of the base of formula (I) and its hydrochloride which makes it possible to prepare these compounds in good yield and in a simple manner, even on an industrial scale.

It has now been found that this object can be fully achieved when the general formula (VI) h3C \ r —- i / N-H2C-S ^ / A-CH2-S- (ch2) 2-NH-C | -SR <VI 1-2H [5-dimethylaminomethyl-2- (furylmethylthio) ethyl] -N- (substituted thio) -2-nitroethylene according to> H3CO CH-NO2, wherein R represents an optionally substituted alkyl or oxoalkyl group such as also an aryl, aralkyl or oxoaralkyl group, is converted in situ to the formula (VII) 5 90419 ΗΑ 90ηΊ / N-H2C-4s ^ 'CH2 “S- (CH2) 2-N = C = CH-NO2 (VII) h3c0 1- {2- [5-Dimethylaminomethyl-2- (furylmethyl-thio) -ethyl] -3-nitroketenimine in a simple manner and in excellent yield and then the keteneimine of formula (VII) is reacted with methylamine.

This finding is surprising for several reasons. Until now, the nitroketene imine of formula (V) having a simple structure, presented in connection with method "B" in the literature, has only been known for a short time. It has not been foreseen that a nitroketeneimine of formula (VII) with a rather complex structure can be formed from a compound of general formula (VI) in a very short time (i.e. within a few minutes) without modifying the moieties not involved in the starting compound of general formula (VI). and not to the intended reaction of the product of formula (VII) formed; likewise not ... it could be assumed that a nitroketeneimine of formula (VII) of complex structure undergoes an addition reaction with methylamine in a very short time to give a base of formula (I) in very high purity and according to our observations with almost no side reaction.

The present invention therefore relates to a new process for 1- [2- [15-dimethylaminomethyl-2- (furylmethylthio) ethyl]] amino. for the preparation of 1-methylamino-2-nitroethylene and its hydrochloride by a process according to which 1- (2- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl] -N-amino-1- (substituted thio) -2-nitroethylene, wherein r represents an alkyl group containing 1 to 4 carbon atoms, 6 90419 is reacted with a silver salt or silver oxide capable of forming a mercaptide, in an organic solvent, optionally in the presence of an acid scavenger, then prepared in situ ( VII) 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl]} - 3-nitroketenimine is reacted with methylamine and finally, if desired, the base of formula (I) obtained is purified, purified and / or, if desired, converted into the hydrochloride .

The intermediate of formula (VII) formed as an intermediate in the process of the invention is novel. The formation of this compound is supported by the fact that 1 - [2 - [5-dimethylaminomethyl-2- (furylmethylthio) ethyl]} - amino-1-methylthio-2-nitroethylene (compound of formula (IV)) and silver nitrate the interaction yields the silver methylmercapide in almost quantitative yield, as shown below.

A compound of general formula (VI) used to prepare a compound of formula (VII), namely a compound of formula (IV), can be considered as a known substance when the general formula shown in the process variant of claim 37 (p. 7) of DE 2,734,070 is compared with Example 24 (p. 68), although no properties of this substance (including chemical: name) have been shown. No other compound of formula (VI) is mentioned in this patent application. According to Example 1 of EP-A-0.002,930, The compound of formula (VI) melts at 71 ° C. To our knowledge, no other compound of formula (VI) has been reported in the literature, thus the compounds of general formula (VI) are new except for the compound of formula (IV). the compounds can be prepared in a known manner by reacting a base of formula (II) with a base of formula (VIII) 7 90419

? S-R

O 2 N-CH = Cl 2 (VIII)

S-R

wherein R is as defined above.

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

As a compound of general formula (VI), a compound of formula (IV) is useful, for example, for the preparation of a nitroketene imine of formula (VII). Metal salts, metal oxides or finely divided metals can be used as substances capable of cleaving mercaptan.

It is customary to use, for example, silver nitrate or copper chloride as metal salts. Organic bases are suitable acid scavengers. Both the formation of the compound of formula (VII) and the reaction with methylamine are preferably carried out at room temperature or at a slightly lower temperature. Organic solvents such as lower aliphatic alcohols can be used advantageously.

In a preferred embodiment of the invention, a solution or suspension of a compound of formula (IV) in absolute ethanol is treated with silver nitrate at 5-30 ° C and methylamine is added directly after precipitation of the formed silver mercaptide, then the reaction mixture is filtered, the solvent is removed from the filtrate and the residue is final. a base of formula (I) in addition to a suitable salt of methylamine. If desired, the ranitidine thus obtained can be recrystallized and, if desired, converted to its hydrochloride.

In another preferred embodiment of the invention, an ethanolic methylamine solution containing silver nitrate is added dropwise to an ethanolic suspension of a compound of formula (IV) and then the above procedure is followed.

The advantages of the methods according to the invention can be summarized as follows: Both steps of the method according to the invention, i. formation of the compound of formula (VII) and reaction with methylamine, proceeds rapidly at room temperature or slightly below. As a result, the compound of formula (VII) remains stable and does not decompose, so that the base of formula (I) formed is free of impurities formed by decomposition products. Another result is energy savings. Due to the short processing time (manufacturing cycle), the equipment can be used efficiently.

- Rapid progress of the reaction is possible largely due to the fact that methylamine, which is in gaseous form under normal conditions, can be used as a possible excess and after the reaction this excess can be easily removed without heat. In stark contrast to this, when the base of formula (I) is prepared using the above-mentioned literature method "B", i. by converting a compound of formula (IX) to a nitroketeneimine of formula (V) and subjecting the latter to an addition reaction with a base of formula (II), the base of formula (II) can only be used in a stoichiometric amount and thus the addition reaction cannot be accelerated by using a compound of formula (II) excess of the base according to the invention, since this base is unstable, sensitive to heat, it can only be removed under high vacuum at a higher temperature and partial decomposition of the base cannot be avoided during distillation. The base of formula (I) thus obtained is heavily contaminated either by the residual amount of base or by the decomposition products formed in the distillation of the excess base of formula (II).

990419 - In contrast to the literature method "A", in which one mole of methyl mercaptan is released in each step, this gas is bound in the form of a harmless, non-volatile methyl mercaptide in the process according to the invention and thus does not pollute the environment.

- The yield of the crude base of formula (I) obtained in the process according to the invention is almost quantitative. This crude product contains only a very small amount of impurities (except for the salt of the acid scavenger used). Using a simple purification method, a completely homogeneous base of formula (I) is obtained, which can be used for the formation of the hydrochloride, in very good yield (about 75%). The hydrochloride thus obtained no longer needs to be purified.

Based on these considerations, the process according to the invention can be used for the preparation of the base of formula (I) and its hydrochloride simply in good yield, also on an industrial scale.

The method according to the invention is explained in detail by means of the following examples.

- Example 1 Preparation of 1- {2- [5-dimethylaminomethyl-2- (furylmethyl spore) -ethyl] -N-amino-1-methylamino-2-nitroethene (base of formula (I)) 51.0 g (0, 30 moles) of silver nitrate dissolved in 4000 ml of absolute ethanol are added at 10 ° C per minute to a solution of 99.5 g (0.30 moles) of 1 - {- 2- [5-dimethylaminomethyl-2- ( (phenylmethylthio) -ethylamino-1-methylthio-2-nitroethylene (compound of formula (IV)) in 2500 ml of absolute ethanol to form silver methyl mercaptide immediately. 557 ml of a 29.2% ethanol solution of methylamine are then added and the mixture is stirred at room temperature for 2 hours. The precipitate (which is silver methyl mercaptide 98.1 ίο 90 4 1 9% in composition and weight) is filtered off 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, adjusting the pH to 10 if necessary. The organic phases are combined, dried and evaporated under reduced pressure. Crude ranitidine is obtained as an evaporation residue in a yield of 79 g (84%).

To prepare the hydrochloride, the crude ranitidine base is dissolved in 380 absolute absolute ethanol and the pH of the solution is adjusted to 5.5 by adding a concentrated aqueous solution of hydrochloric acid at 0-5 ° C. The mixture is stirred at 0 ° C for another 40 minutes.

The crystalline precipitate is filtered off, washed with ethanol and dried to give ranitidine hydrochloride in a yield of 57.45 g (54.6%), m.p. 143 ° C. A second batch of 31.15 g is obtained from the mother liquor, m.p. 143 ° C.

The starting material 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl]} amino-1-methylthio) -2-nitroethylene (compound of formula (IV)) can be prepared e.g. 0.002,930 according to Example 1.

Example 2 1- {2- [5-Dimethylaminomethyl-2- (furylmethylthio) -ethyl] | Preparation of -amino-1-methylamino-2-nitroethylene (base of formula (I)) and its hydrochloride

A solution of 2.55 g (0.015 mol) of silver nitrate in 200 ml of absolute ethanol is added to a solution of 5 g (0.015 mol) of 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl]} -amino-1-methylthio-2-nitroethylene (compound of formula (IV)) in 125 ml of absolute ethanol, stirring for 1 minute at 6 ° C to form silver methyl mercaptide immediately. The mixture is stirred at 5 [deg.] C. for a further 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.

n 90419

The filtrate is left to stand at 5 ° C overnight, filtered again and the filtrate is evaporated at room temperature under reduced pressure. To the residue is added 50 ml of water, after which the pH is adjusted to 5.5 by adding 1N aqueous hydrochloric acid. The mixture is extracted twice with 70 ml of dichloromethane, then the pH of the aqueous phase is adjusted to 10 by adding 1N sodium hydroxide solution and extracted four times with 70 ml of dichloromethane. 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 off and dried, yielding 3.02 g (64.0%) of the intended base, m.p. 68-70 ° C. After repeated evaporation of the mother liquor and recrystallization of the residue, a further 0.55 g (11.2%) of the intended base are obtained.

The base prepared according to Example 2 can be converted into its hydrochloride, e.g., as follows.

3.5 g of crude ranitidine are dissolved in 17.5 ml of absolute ethanol and the pH of this solution is adjusted to 5 to 5.5 by adding concentrated hydrochloric acid at 0 ° C with stirring. The mixture is stirred at 0 ° C for a further 40 minutes and then left to stand at 0-5 ° C overnight. The crystalline precipitate is filtered off, washed with ethanol and dried to give 3.72 g (84.4%) of the intended hydrochloride, m.p. 143 ° C.

Example 3 Preparation of 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) -ethyl] -N-amino-1-methylamino-2-nitroethylene (base of formula (I))

A solution of 0.85 g (0.005 mol) of silver nitrate and 10 ml of ethanolic methylamine solution is added to 1.66 g (0.005 mol) of 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) with stirring at room temperature. -ethylamino-1-methyl-thio-2-nitroethylene (compound of formula (IV)) suspended in 10 ml of absolute ethanol. The mixture is stirred at room temperature for a further 30 minutes, then filtered and evaporated under reduced pressure. The work-up is carried out as described in Example 2 to give 1.21 g (77.1%) of the intended base, m.p. 68-70 ° C.

Example 4 Preparation of 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) -ethyl] -amino-1-methylamino-2-nitroethylene (base of formula (I))

A solution of 0.85 g (0.005 mol) of silver nitrate in 60 ml of allyl alcohol is added portionwise over 2-3 minutes at 8-10 ° C with stirring to a solution containing 1.66 g (0.005 mol) of 1- (2 - [5-dimethylaminomethyl-2- (furylmethylthio) ethyl]} -amino-1-methylthio-2-nitroethylene (compound of formula (IV)) in 20 ml of allyl alcohol, then 8 ml of an ethanolic solution of methylamine in the same at 1-2 minutes and the mixture is stirred at room temperature for 2 hours Finishing is carried out as described in Example 2 to give 0.95 g (60.5%) of the intended base, mp 70-72 ° C.

Example 5 Verification test

The following verification experiment was performed to show that in the process of the invention 1- {2- [5-dimethylaminomethyl-2- (furylmethylamino) ethyl] -N-amino-1-methylthio-2-nitroethylene (compound of formula (IV)) ) first reacts with silver nitrate and then, while precipitating the silver methyl mercaptide, the resulting 1-2-C5-dimethylaminomethyl-2- (furylmethylthio) ethyl] -3-nitroketenimine (compound of formula (VII)) reacts with methylamine. with.

The procedure of Example 1 was followed except that the precipitate formed in the solution after the addition of silver nitrate was filtered, washed, dried and analyzed. The precipitate weighed 2.28 g (98.1%).

i3 9041 9

Analysis for Cl 2 AgS (MW 154.98) calculated: C 7.75%, H 1.95%, Ag 69.6% Found: C 7.69%, H 1.36%, Ag 69.1 %.

Claims (2)

1. Menial Carbon H3S S7Π N-H2C-1NO ^ -CH2-S- (CH2) 2-NH- (j: -NH-CH3 (I) H3C / ^ CH-NO2 mukaisen 1- {2- (5-dimethylaminomethyl) -2- (furyylimethylthio) ethyl]} amino-1-methylamino-2-nitroethenine and then hydrochloridine valmistamisexi, tunnettu siitä, etaataatatet ylisen kaavan (VI) H3C XN-H2C- ^ P ^ -CH2-S- ( CH 2) 2-NH- (1 H -SR (VI) h 3 C 2 O 2 -CH 2 mucaine 1- {2- [5-dimethylaminomethylmethyl-2- (furyylimethylthio) ethyl]} amino-1- (substituthio) -2 -nitroeteeni, jossa kaavassa R merkitsee alkyyliryhmää, joka sisältää 1-4 hiiliatomia, reagoimaan sellaisen hopeasuolan tai hopeaoxidin chance, .joka pystyy caravan (VII) H3C r-, N-H2C-10 O> Lch2-S- (CH2) 2-N = C = CH-NO2 (VII) ... / ^ cr h3c mucaine l- {2- [5- dimethylamylaminomethyl-2- (furyylimethylethylthio) ethyl]} - 3-nitroceteenimimini reagoimane methyliaminine chance and lopuksi haluttaessa erotetane s aatu kaavan (I) mukainen emäs, puhdistetaan se ja / tai haluttaessa muunnetaan se sen hydrochloridiksi. ie 9041 9 A process for the preparation of 1- {2- [5-diraethylaminomethyl-2- (furylmethylthio) ethyl]} amino-1-methylamino-2-nitroethylene of formula (I) h3cx-N-H2c-O ^ 1 2 -S- (CH 2 ) 2 - NH - 3 - NH-CH 3 (I) h 3 C 2 -CH 2 and hydrochloride salts thereof, characterized in that 1- {2- [5-dimethylaminomethyl-2- (furylmethylthio) ethyl]} amino-1- (substituted the thio) -2-nitroethylene of formula (VI) H 3 Cl 2 / N-H 2 Cl-1SP / J ~ CH 2 -S- (CH 2) 2 -NH- (j) -SR (VI) h 3c ° CH-NO 2 alkyl group of 1-4 carbon atoms, reacted with a silver salt or a silver oxide which precursor to form a mercaptide, in an organic solvent, optionally in the presence of a substance which binds acid, then the in situ prepared 1- {2- [5 -dimethylaminomethyl-2- (furylmethylthio) ethyl] -3-nitroketenimine of formula (VII) ΐ H3CX Joi N-H2C-A W / -CH2-S- (CH2) 2-N = C = CH-NO2 (VII) ) H3 </ 0 with methylamine and finally, if desired, the resulting base of formula (I) is separated, purified, and / or, if desired, transferred to its hydrochloride. Process according to claim 1, characterized in that, as an organic solvent, a lower aliphatic alcohol is used.