The present invention relates to a process for the preparation of compounds with antiulcer action , specifically the compounds having the following general formula :

X

II

Ar-CH -S- ( CH ) -NH-C-NH-R (V)

2 2 n 1 wherein R represents hydrogen, alkyl , alkyl substituted with a single or substituted aromatic ring or with a single or substituted heterocyclic ring, Ar represents a single or substituted aromatic ring or heterocycle, n=l, 2, 3, 4, 5 or 6 and X represents CH-NO S,N-C=N. Compounds covered by the above general formula and well known include: (I) ranitidine, for which in the above formula:

1.2 ) niperotidine, for which;

(3) cimetidine, for which:

The therapeutic importance of the compounds in question makes any improvement in the process and/or yield of extreme interest.

The primary object of the present invention is to perfect a synthesis

method for the compounds of the general formula (V) .

Said object is achieved by a process characterized by the stages: a) reaction of a carba ate of the formula

_ _N H- ⁰ C-0 ^H ' ^hal °9en , ^NO

(VIII )

with a bisdithio-alkylamine of the formula:

K-N-(CH ) -S-S-CCH ) -NH_ ( IX)

2 2 n 2 n . to obtain a urea of the formula

0 0

II II

E -NH-C- H-CCH ) -S-S-(CH ) -NH-C-NH-R ( I)

1 2 n 2 n 1 where R , n have the abovementioned meanings. b) reaction of the urea of formula (I) with a compound capable of converting it into the corresponding bis-carbodiimide of the formula:

R -N=C=N-(CH ) -S-S-CCH ) -N=C=N-R (II)

1 2 n 2 n 1 c) reaction of the carbodiimide of formula (II) with a compound selected from among nitromethane in the presence of a strong base and a saline derivative of the cyanamide to form the product of formula:

X X

II II

E^NH-C-NH-CCH ) -S-S-(CH ) -NH-C-NH-R (III) where X= CH-NO ; N-C=N 2 d) reaction of the compound of formula (III) with a compound with reduces the —S—S— group to obtain a compound of formula:

X

8

R -NH-C-NH-(CH ) -SH (IV)

1 2 n e) reaction of the compound of formula (IV) with a reactant of formula

Ar-CH -Cl to obtain the desired products of formula:

R -NH-C-NH-(CH ) -S-CH -Ar (V)

1 2 n 2 wherein R , X, Ar and n have the above meanings.

As appears from the above schematization the process in accordance with the invention makes it possible to obtain raniditine, niperotidine or cimetidine directly depending on the meaning of R , Ar, X and n.

From the following examples it can be readily seen that among the principal advantages of the present invention are to be counted process simplification and obtaining quantitative yields since the only obstacle to achievement of the latter advantage resides in the possible impurities of the reactants.

Now considering in detail the process of the present invention, synthesis of the urea of formula (I) (stage (a)) is carried out by reacting a carbamate of formula (VIII) dissolved in the solvent at a temperature of between approximately 40°C and 50°C with a compound of formula (IX) which has been freed from the hydrochloride by treatment with aqueous soda.

The solvent must be capable of solubilizing the urea (I) and have a certain miscibility with water.

Preferably this is pyridine and the aqueous soda solution utilized to liberate compound (IX) from the hydrochloride must be the minimun quantity possible since v/ater would cause the urea (I) to precipitate again.

Concerning syntheis of compound II (stage (b)) it is first of all pointed out that the reactants capable of converting the urea (I) into the corresponding carbodiimide (II) are selected from among triphenylphosphine (Ph P), sulfuryl chloride (SO Cl ) and thionyl chloride (SoCl ) . In the case of the triphenylphosphine, bromine must also be present and in all cases an acid acceptor, preferably an organic base, and still more preferably triethyla ine, must be present.

The reaction solvent is an aprotic solvent, preferably a chlorinated hydrocarbon such as dischlorome hane, chloroform and others.

The reaction is carried out at low temperature and performed by introducing very slowly at a temperature on the order of 5°C small portions of the urea (I) in a reactant already formed in the reactor starting from the compound selected from among triphenylphospine, thionyl

chloride or sulfuryl chloride dissolved in the reaction solvent and having (if necessary) added bromine and the acid acceptor, specifically triethylamine.

The abovementioned reactant is also formed at low temperature, specifically below 0°C, and introducing slowly the different reactants.

Once all the urea (I) has been added, the temperature is allowed to rise again spontaneously to room temperature and the reaction mixture is reacted while stirring for approximately 1-2 hours, after which the carbodiimide is isolated in a known manner.

Preferably the reactant into which the urea (I) is introduced is in excess of the stechiometric quantity necessary for conversion.

In the third reaction stage (c) , when it is desired to prepare compound

(III), the carbodiimide (II) in solution in a polar aprotic solvent, preferably dipolar such as dimεthylformamide or dimethylsulfoxide, is added slowly at room temperature to a solution of nitromethane in the same solvent, prepared previously and containing a strong base such as for example sodium hydride.

Preferabl3τ the nitromethane is in molar excess of the carbodiimide.

Once addition of the latter has been terminated, the reaction is completed in 15—20 hours at a temperature of approximately 40°C with quantitative yields if the reactants are free of impurities.

If it is desired to prepare cimetidine, compound (II) is reacted with a saline derivative of cyanamide, preferably sodium salt.

In the fourth stage (d) of the synthesis, to the compounds of formula

(III) are applied appropriate methods of reduction of the disulfide bridges known in the literature to obtain the compounds of formula (IV) .

They are preferably treated with for example sodium borohy ride.

The reaction solvent is a mixture of water and alcohol and preferably the alcohol is me hanol, with an excess of alcohol.

In the fifth and last stage (e) the compounds of formula (IV) are reacted with a halogenide of formula (VI) if it is desired to obtain ranitidine and niperotidine and when the substituent X= CH-NO or with a halogenide

of formula (VIII) if it is desired to obtain cimetidine when the substituent X=N-C=N.

In all cases the reaction is carried out in polar aprotic solvents and preferably dipolar ones such as dimethylformamide and dimethylsulfoxide. The reaction is carried out by introducing a solution of the halogenide (VI) or (VII) freed from the hydrochloride for treatment with an appropriate base, preferably sodium hydride, in a solution containing the sodium salt at the group SH obtained by reaction of the compounds (IV) with an appropriate base, preferably sodium hydride.

After this introduction the reaction mixture is brought to a temperature of approximately 70-80°C for 1-3 hours, then cooled to room temperature. Yields are quantitative if the reactants are free of impurities. The reaction mixture is concentrated in a vacuum to eliminate the solvent and then the raw product of formula (V) goes to the purification process. An example will now be given relative to the preparation of the niperotidine, it being understood that it is intended merely as illustrative and non limiting of the synthesis of which a general scheme is given.

mi <X, o H N-CH -CH -S-S- :H -CH -NH 2 2 2 2 2 o

pyridlne

NIPEROTIDINE

EXAMPLE A

N,N'-di^N-(3,4-methylenedioxybenzyl)-carbamoyl/2,2 '-dithiobisethanamine.

In a 500 ml 3-necked flask equipped with a stirring mechanism are placed

40 g of 0-phenyl-N(3,4-methylenedioxybenzyl)-carbamate and 150 ml of pyridine. The reaction mixture is then brought to 45°C.

An aqueous solution (32ml) containing 16.5 g of cystamine dihydrochloride and 5.88 g of sodium hydride is prepared separately.

The aqueous solution is dropwise added to the pyridine solution and at the end the reaction mixture is heated to 90-95°C for approximately 20 hours. After cooling (with precipitation of a white substance) the reaction mixture is poured into 400 ml of water and after 2 hours of vigorous stirring the precipitated product is filtered and washed with water made acidic with acetic acid.

The product is repeatedly slurried in water and filtered to eliminate traces of pyridine, then it is poured into 60 ml of acetone to eliminate traces of phenol. It is filtered and vacuum dried at 60-70°C for 12 hours.

33 g of product are obtained with a yield of 88.7% and the melting point is 181-183°C.

TLC control (Merck 5554); (eluent : ethyl acetate/n-hexane 1:1)

Detector: UV, cerium phosphomolybdate.

Rf= 0.78

EXAMPLE B 1,1 '-di/(3,4-methylenedioxybenzyl)carbodiimidyl/ ,2'-dithiobis-ethane.

(2)

In a 250 ml 4-necked flask equipped with a stirring mechanism, a termometer and a filling funnel are placed 80ml of CH Cl and 15.5g of

Ph P until a clear colorless solution is obtained. The Br„ (3ml dissolved 3 2 in 10 ml of CK Cl ) is introduced very slowly at a temperature of between

0 and 10°C. The reaction mixture is stirred for further 30 minutes, then the product obtained in example A(10g) is added in portions while holding the temperature bet.veen 0 and 5°C. At the end of the addition after approximately 1 hour the added product is completely solubilized. IR analysis is performed and a peak corresponding to the carbodiimide at

2120 cm is found. The reaction mixture of a dark yellow colour contains

Et NH3r is suspension. It is stirred again for 1 hour while allowing the temperature to rise again spontaneously to 20°C.

It Is vacuum concentrated at a temperature below 30°C to approximately half original volume. The Et NHBr formed is filtered, then the filtered

3 solution is concentrated to dryness to obtain an oily residue consisting of carbodiimide and Ph P0.

3

28.8 g of mixture are obtained. Theoretical yield of diimide + Ph P0 is 25.6g.

EXAMPLE C , 'di/N-(3,4-methylenedioxybenzyl)-l-amino-2-nitro-etheny_l/-2 ,2'-dithio- bis-ethanamiπe.

In a 250 ml 3-necked flask are placed 80ml of dimethylsulfoxide and 1.8 g of sodium hydride. The mixture is stirred for 10 minutes and CH NO (3.2

3 2 ml) is added.

After stirring at room temperature for 3 hours a yellow heterogeneous reaction mixture is obtained. The carbodiimide (9.2 g) previously obtained and dissolved In 20 ml of dimethylsulfoxide is introduced drop by drop at room temperature while stirring well. After completion of the

addition (20 minutes) the mixture is brought to 35°C and stirred for 15 hours. IR control checks are performed at 30 minute intervals for disappearance of the band corresponding to the carbodiimide, the peak of which disappears completely after 2 hours. The reaction mixture is vacuum concentrated to a small volume at a temperature of approximately 80°C to obtain an oily residue which is purified by partitioning between chloroform and water (elimination of salts, removal of the residual DMSO and water soluble bi-products) . The dried chloroform phase (anhydrous

Na SO,) is concentrated to dryness to obtain a brown solid residue which is dissolved in 100 ml of acetone and acidified with an excess of acetic acid.

After fi ltration of the prec ip i tate formed , 5. 7 g ( 47% yi eld ) of a crystal l ine product ( 3 ) are obtained .

TLC control ( Merck , eluent : ethyl acetate/methanol/NH OH 9/0 . 5/0.1 ) : Rf

4 lcwer than that of the starting product obtained in example A ( UV de tector) . Melting point is 213-215°C

EXAMPLE D N- ( 2-mercap toethyl ) -N ' - ( 3 , 4-methyl enedioxybenzyl ) -2-nitro-l , 1-ethenedi a-

In a 100 ml 4-necked flask under a nitrogen atmosphere are placed ethanol (25ml), water (5 ml) and 5.5 g of the product obtained in example (C) .

1.05 g of NaBH are added slowly in small portions. Hydrogen is developed intensely and regularly. At the end of the addition stirring is continued at 45-50°C for 18 hours. The heterogeneous yellow reaction mixture is poured into water. The precipitate formed is filtered and placed in an oven to dry. 4.8 g of product are obtained with a yield of 87.8%. TLC control (Merkc 5554; eluent: ethyl acetate/methanol/H 0 9/0.5/0.1). Detecotr: cerium phospho olybdate. The product (4) becomes pale blue.

Melting point is 236-238°C.

EXAMPLE E N- 2-/775- T dimethylamino )-methyl7-2- uranyl7methyl7thio7ethyl7- ' - ( 3 , 4-me thylenedioxybenzyl ) -2-nitro-l , l-ethylenediamine (niperotidine)

In a 100 ml 3-necked flask equipped with a thermometer and mechanical stirring are placed 20 ml of dimethylformamide to which are added 0.5 g of NaOH in a nitrogen atmosphere. After 10 minutes of stirring at room temperature 4g of the product obtained in example D divided in four lg portions are added at 15-minutes intervals. At the end of the addition the mixture Is stirred at room temperature for approximately 1 hour. Then 3,38g of 5-dimethylamInomethyl furfuryl chloride separately freed from the hydrochloride with 0.53 g of NaH in dimethylformamide (20ml) are added. At the end of the addition the mixture is heated to 70-75°C for 1 hour, then cooled to room temperature. The reaction mixture is concentrated to a small volume. The residue is purified by partitioning between 50 ml of water and 50 ml of chloroform to eliminate the salts. The chloroform phase Is filtered, made anhydrous (anhydrous Na SO ) and concentrated to dryness. An oily substance (4.8g ) Is obtained which is dissolved In 15 g of ethylacetatε and held below 0°C. A crystalline precipitate (3g) is formed with 51% yield. Melting point: 113-115°C. TLC control (Merck 5554., eluent: ethyl acetate/methanol/NaOH 9/0.5 0.2; detector; iodine or cerium phosphololybdate) . Rf= 0.2 The IR spectrum (KBr) of the final product corresponds to the reference compound.