Process for preparing salcaprozate sodium

Abstract

Process for preparing salcaprozate sodium comprising a condensation step carried out in a biphasic mixture comprising an organic phase and an aqueous phase. Advantageously, the use of a biphasic mixture during the condensation reaction prevents the partial hydrolysis of the compound of Formula III contained in the organic phase, thus obtaining a higher conversion and reaction yield. Furthermore, by avoiding hydrolysis of the compound of Formula III, the amount of 2-acetoxybenzoic acid being formed and which remains as an impurity in the compound of Formula V is very low.

Description

[0001] PROCESS FOR PREPARING SALCAPROZATE SODIUM .

[0002] Field of the invention .

[0003] The present invention concerns a process for preparing salcaprozate sodium of Formula I : Formula I .

[0004] Prior art .

[0005] Salcaprozate sodium ( SNAC ) is used as an excipient in the formulation of drugs with the function of enhancing chemical permeation and therefore to favour the oral absorption o f macromolecules , peptides and proteins such as insulin ( diabetes ) , heparin (heart attacks and angina ) and cyanocobalamin (vitamin B12 deficiency and anaemia ) that would otherwise have a poor bioavailability . SNAC is considered safe for human consumption by the Food and Drug Administration ( FDA) .

[0006] Patent application WO 96 / 30036 concerns pharmaceutical compositions useful in the administration of active agents , such as biologically or chemically active peptides , for example calcitonin and insulin; polysaccharides or mucopolysaccharides , for example heparin; antibiotics or other organic substances . These active agents , i f not properly conveyed, are rapidly deactivated or destroyed in the gastrointestinal tract by acid or enzymatic hydrolysis . To avoid such drawbacks , at least one organic acid ( or a salt thereof ) having in its chemical structure an aromatic amide with a hydroxyl group in the ortho position of the aromatic ring and a lipophilic chain with a number of carbon atoms ranging from 4 to 20 is added to the pharmaceutical compositions . Among the organic acids having the above chemical structure , the salcaprozate sodium of Formula I has demonstrated particular ef ficacy as a vector for the delivery of the active agents in the selected biological systems .

[0007] The procedure reported in WO 96 / 30036 requires the use o f an aqueous solution of a metal hydroxide , in particular o f sodium hydroxide , as a solvent in the condensation step between 8-aminooctanoic acid of Formula IV and 2-acetoxybenzoic acid chloride of Formula I I I to prepare the intermediate of Formula V :

[0008] Formula III Formula IV Formula V

[0009] However, the water present in the reaction medium causes the partial hydrolysis of the compound of Formula I I I with consequent low reaction yield and formation o f 2- acetoxybenzoic acid which remains as an impurity in the compound of Formula V, which must therefore be puri fied, with further reduction of the overall yield of the process .

[0010] Patent application CN111978193 describes a method for the preparation of sodium salcaprozate in which salicylic acid is reacted with 8-aminooctanoic acid .

[0011] Patent application WO 2001 / 070219 describes another synthetic route for preparing salcaprozate sodium, which comprises a step of alkylation of a protected / activated salicylamide by reaction with a dicarboxylate as alkylating agent . This synthesis process involves a step that is carried out at a temperature of 140 ° - 150 ° C, with obvious energy expenditure and therefore increase in the production costs . In addition, the use of high amounts of organic solvents is required and reaction times are long . Finally, the solid intermediates of this process are poorly crystalline and difficult to filter, with consequent difficulties m eliminating impurities from the finished product.

[0012] Therefore, the need is felt to have an improved process for preparing salcaprozate sodium, which is easy to achieve at an industrial level.

[0013] The Applicant has overcome such problems through a process comprising a condensation step carried out in a biphasic solvent mixture, as better illustrated below. This process makes it possible to obtain high-purity salcaprozate sodium, with high process yields and reduced preparation times, such that they make it suitable for industrial-scale production. Summary of the invention.

[0014] The present invention therefore concerns a process for preparing salcaprozate sodium of Formula I: Formula I, wherein said process comprises: a) reacting a compound of Formula IT: Formula IT with a chlorinating agent in a water-immiscible organic solvent to obtain an organic solution of a compound of Formula ITT: Formula ITT in said water-immiscible organic solvent; b) reacting a compound of Formula TV: Formula TV with a base in aqueous solution to obtain an aqueous solution of a salt of Formula IV-A: Formula IV-A where M+ is a cation of an alkaline or alkaline-earth metal ; c ) reacting the organic solution of the compound o f Formula I I I obtained from step a ) with the aqueous solution o f the compound of Formula IV-A obtained from step b ) to obtain a biphasic mixture comprising an organic phase and an aqueous phase , wherein a compound of Formula V-A: Formula V-A is dissolved in the aqueous phase ; d) separating the aqueous phase containing the compound of Formula V-A from the organic phase of the biphasic mixture obtained in step c ) and adding an acid to the aqueous phase to obtain a compound of Formula V : Formula V e ) reacting the compound of Formula V with an inorganic base containing Na+ to obtain salcaprozate sodium of formula ( I ) •

[0015] Advantageously, the use of a biphas ic mixture during the condensation reaction described in step c ) prevents the partial hydrolysis of the compound of Formula I I I contained in the organic phase , thus obtaining a higher conversion and reaction yield . Furthermore , by avoiding hydrolysis of the compound of Formula I I I , the amount of 2-acetoxybenzoic acid being formed and which remains as an impurity in the compound of Formula V is very low .

[0016] Advantageously the intermediates o f the process according to the present invention are easily filterable crystalline solids and the filtration times are fast . So the industriali zation of the new process is simpli fied .

[0017] Furthermore , the process according to the present invention is environmentally advantageous since it uses a reduced amount of organic solvents per kilogram of salcaprozate sodium produced . It can therefore be classi fied as a "green process" .

[0018] Further features and advantages of the present invention will be apparent from the following detailed description . Detailed description of the invention .

[0019] For the purposes of the present invention, in the following description and claims the definitions of numerical ranges comprise the individual values within the range itsel f and the corresponding extremes , unless otherwise speci fied . For the purposes of the present invention, in the following description and claims the term "comprising" also includes the terms "constituted by" or "constituted essentially by" .

[0020] Synthesis scheme .

[0021]

[0022] Formula IV Formula IV- A

[0023] Formula V Formul a I

[0024] List of abbreviations.

[0025] DMF: dimethyl formamide NaOH: sodium hydroxide or soda

[0026] HC1 : hydrochloric acid

[0027] EDTA: ethylenediaminetetraacetic acid

[0028] SOC12: thionyl chloride

[0029] PCI3: phosphorus trichloride PCI5: phosphorus pentachloride

[0030] DIPEA: N-ethyl-diisopropylamine

[0031] HMDA: hexamethylenediamine

[0032] NaHSO3 : sodium hydrogen sulphite.

[0033] Preferably, in step a) the chlorinating agent is selected from: thionyl chloride (SOC12) , phosphorus trichloride (PC13) , phosphorus pentachloride (PC15) , oxalyl chloride. More preferably, the chlorinating agent is thionyl chloride.

[0034] Preferably, in step a) the organic solvent is a water- immiscible chlorinated solvent, selected for example from methylene chloride, chloroform, carbon tetrachloride, or mixtures thereof; more preferably it is methylene chloride. Alternatively, the organic solvent is preferably a water- immiscible ether, for example t-butyl methyl ether. Alternatively, the organic solvent is a water-immiscible aromatic hydrocarbon, preferably selected from toluene, xylene, benzene; more preferably it is toluene.

[0035] Advantageously, in step a) a catalyst is added, preferably selected from: dimethylformamide (DMF) , pyridine, N-ethyl- diisopropylamine (DIPEA) , hexamethylenediamine (HMDA) . More preferably, the catalyst is DMF.

[0036] Preferably, in step a) the temperature is comprised between 35 °C and 60 °C, more preferably between 40 °C and 50 °C.

[0037] Preferably, in step a) the molar ratio of chlorinating agent to compound of Formula II is comprised between 1.10 and 1.50, more preferably between 1.20 and 1.40.

[0038] Preferably, in step a) the reaction time is comprised between 0.5 hours and 5 hours, more preferably between 1 and 3 hours .

[0039] Preferably, in step b) the base in aqueous solution is a hydroxide of an alkaline or alkaline-earth metal, more preferably a hydroxide of an alkaline metal, even more preferably is sodium hydroxide (NaOH) . Preferably the aqueous solution of NaOH has a concentration (w / w) comprised between 5% and 15%.

[0040] Preferably, in step b) the reaction temperature is lower than 30 °C, preferably lower than 25 °C. Preferably in step b) the reaction time is equal to at least 20 minutes.

[0041] Preferably, in step c) the molar ratio of the compound of Formula IV-A to the compound of Formula III is comprised between 1.20 and 1.40, more preferably between 1.25 and 1.35.

[0042] Preferably, in step c) the organic solution of the compound of Formula III prepared in step a) is mixed with the aqueous solution of the compound IV-A prepared in step b) at a temperature comprised between -5 °C and 10 °C, more preferably between 0 °C and 5 °C.

[0043] Preferably, in step c) the organic solution of the compound of Formula III prepared in step a) is added to the aqueous solution of the compound IV-A prepared in step b) by dropping, with a dropping time comprised between 2 and 4 hours, more preferably between 2.5 and 3.5 hours.

[0044] Preferably, in step c) the organic solution of the compound of Formula III prepared in step a) is added to the aqueous solution of the compound IV-A prepared in step b) by dropping, at a temperature comprised between -5 °C and 10 °C, more preferably between 0 °C and 5 °C, and with a dropping time comprised between 2 and 4 hours, preferably between 2.5 and 3.5 hours .

[0045] Preferably, in step c) the reaction is carried out by stirring for a time equal to at least 1 hour at a temperature from 0 °C to 5 °C.

[0046] Alternatively, in step c) the reaction is preferably carried out by stirring for a time comprised between 6 and 10 hours, more preferably between 7 and 9 hours, at a temperature between 15 °C and 30 °C, more preferably between 20 °C and 25 °C.

[0047] Preferably, in step d) an aqueous solution of hydrochloric acid is added to the aqueous phase at a temperature lower than 30 °C, more preferably lower than 25 °C. Preferably, the aqueous solution of hydrochloric acid has a concentration comprised between 5% and 7% by weight.

[0048] Preferably in step d) the acid is added in an amount so as to obtain a pH comprised between 5.8 and 6.2, preferably between 5.9 and 6.1.

[0049] Preferably, in step d) the stirring time after addition of the acid is at least 1 hour.

[0050] Preferably, in step d) the compound of formula V is filtered and then washed with water.

[0051] Preferably, after step d) at least one step d' ) of purifying the compound of Formula V is carried out.

[0052] According to a preferred embodiment, the purifying step d' ) comprises: (i) adding to the compound of Formula V obtained from step d) a base so as to obtain a solution of a carboxylate salt of the compound of Formula V; (ii) adding to said solution a complexing agent which is capable of complexing metal ions present as impurities with the formation of a suspension; (iii) filtering the suspension thus obtained so as to separate complexed metal ions from the solution of the compound of Formula V in the form of carboxylate salt; (iv) acidifying the solution of the compound of Formula V in the form of carboxylate salt so as to precipitate the compound of Formula V which is then separated.

[0053] Preferably, in step (i) the base is a NaOH solution with a concentration comprised between 1.8 M and 2.2 M, more preferably between 1.9 M and 2.1 M. Preferably, the NaOH solution is added under stirring at a temperature lower than 50 °C, more preferably lower than 40 °C. Preferably, at the end of the addition of the NaOH solution, the temperature is comprised between 15° and 30 °C, more preferably between 20 °C and 25 °C. Preferably, in step (i) the stirring time is at least 20 minutes. Preferably, the complexing agent added in step (ii) is selected from: ethylenediaminetetraacetic acid (EDTA) , ascorbic acid, NaHSO3; preferably the complexing agent is EDTA. Preferably, the complexing agent is added in a weight ratio with respect to the compound of Formula V comprised between 0.7% and 1.3%, preferably between 0.8% and 1.2%. Preferably, step (11) is carried out under stirring for a time equal to at least 20 minutes.

[0054] Preferably, the filtration step (iii) is carried out on a filter of inert material selected from cellulose, celite, dicalite, more preferably cellulose.

[0055] Preferably, step (iv) is carried out by adding an aqueous solution of HC1 with a concentration comprised between 1.0 M and 3.0 M, more preferably between 1.1 M and 2.0 M. The amount of acid added is such as to preferably obtain a pH value from 4 to 7, more preferably from 5 to 6.5, even more preferably from 5.8 to 6.2. Preferably, at the end of the addition of the acid, stirring is maintained for at least 1 hour.

[0056] At the end of step (iv) , the compound of Formula (V) is preferably separated by filtration.

[0057] According to another preferred embodiment, the purifying step d' ) comprises: (v) dissolving the compound of Formula V obtained from step d) in a polar organic solvent selected from: R-OH alcohols where R is a straight or branched Ci-Cg alkyl, preferably straight, more preferably the alcohol is methanol; ketones of general formula R1-CO-R2, wherein the groups R1 and R2, equal to or different from each other, are straight or branched Ci-Cg alkyls, preferably R1 is equal to R2, more preferably the ketone is acetone; or mixtures thereof; (vi) adding water to the solution of the compound of Formula V obtained from step (v) so as to precipitate the compound of Formula V which is then separated. Preferably, in step (v) there is present an amount of water comprised between 20% and 40% by weight, more preferably between 20% and 30% by weight, with respect to the weight of the compound of Formula V.

[0058] Preferably, in step (v) the polar organic solvent is added in an amount so as to obtain a weight / weight ratio, of solvent to compound of Formula V, from 3.4 to 4.3, more preferably from 3.7 to 4.2, even more preferably from 3.8 to 4.1.

[0059] Preferably, a temperature comprised between 40 °C and 60 °C, more preferably between 45 °C and 55 °C, even more preferably between 47 °C and 53 °C is maintained during step (v) .

[0060] Preferably, in step (vi) water is added in an amount so as to obtain a weight / weight ratio of water to compound of Formula V from 4.3 to 5.4, more preferably 4.6 to 5.3, even more preferably 4.8 to 5.2. Preferably, in step (vi) , the water is added slowly, for a time generally comprised between 1 and 3 hours, preferably between 1.5 and 2.5 hours. Preferably, at the end of the addition of water, stirring is maintained for at least 30 minutes at a temperature comprised between 45 °C and 55 °C. Preferably, at the end of stirring the temperature is brought to a value comprised between 15 °C and 30 °C, more preferably between 20 °C and 25 °C, and therefore stirring is still maintained for at least 2 hours.

[0061] At the end of step (vi) , the compound of Formula (V) is preferably separated by filtration.

[0062] In a preferred embodiment, the purification d' ) of the compound of Formula V is obtained by a first purifying step according to steps (i)- (iv) above, which is followed by a second purifying step according to steps (v)- (vi) above.

[0063] After separation of the compound of Formula V at the end of the purification, it is preferably dried by heating at a temperature preferably comprised between 40 °C and 85 °C, more preferably 43 °C and 65 °C, even more preferably between 45 °C and 55 °C. The drying time is preferably comprised between 8 and 64 hours, more preferably between 12 and 20 hours, even more preferably between 14 and 18 hours. Preferably, drying is carried out under vacuum.

[0064] Preferably, in step e) the inorganic base containing Nanis selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, more preferably it is sodium hydroxide.

[0065] Preferably, in step e) the compound of Formula V is dissolved in a polar organic solvent selected from: R-OH alcohols, where R is a straight or branched Ci-Cg alkyl group, preferably straight, more preferably the alcohol is ethanol; ketones of general formula R1-CO-R2, wherein the groups R1 and R2, equal to or different from each other, are straight or branched Ci-Cg alkyl groups, preferably R1 is equal to R2, more preferably the ketone is acetone; ethers of general formula R3-O-R4, wherein the groups R3 and R4, equal to or different from each other, are straight or branched Ci-Cg alkyl groups; or mixtures thereof.

[0066] Preferably, in step e) , the polar organic solvent is added in an amount so as to obtain a volume / weight ratio of polar organic solvent to compound of formula V comprised between 1.0 and 5.0, more preferably between 2.0 and 4.0.

[0067] Preferably, in step e) the temperature is comprised between 25° and 50 °C, more preferably between 30° and 40 °C.

[0068] Preferably, in step e) the weight ratio of the inorganic base containing Na+ to the compound of formula V is comprised between 0.12 and 0.16, more preferably between 0.13 and 0.15.

[0069] Preferably, in step e) the stirring time is comprised between 15 minutes and 2 hours.

[0070] Preferably, in step e) an apolar organic solvent selected from straight or branched Cg-Cg alkanes, more preferably straight, in particular heptane, is added to the solution of the compound of Formula V and the inorganic base containing Na+ in a polar organic solvent.

[0071] Preferably, in step e) the apolar organic solvent is added in an amount so as to obtain a volume / weight ratio of apolar organic solvent to compound of formula V comprised between 1.20 and 6.0, more preferably 2.0 and 5.0, even more preferably between 3.0 and 4.0.

[0072] Preferably, in step e) the reaction temperature is comprised between 0° and 20 °C, more preferably between 5° and 15 °C.

[0073] Preferably, in step e) the reaction time is comprised between 30 minutes and 18 hours, more preferably between 1 hour and 16 hours, even more preferably between 2 hours and 12 hours .

[0074] At the end of step e) , the salcaprozate sodium of Formula I can be isolated by conventional techniques, for example by filtration .

[0075] In a preferred embodiment, the salcaprozate sodium in the form of a solution in water and / or in organic solvent can be subjected to a spray drying process, so as to obtain the product in the form of particles having a substantially spherical shape, particularly suitable for use.

[0076] The following examples are provided by way of illustration only, therefore such examples are not intended as limiting the scope of the invention.

[0077] Example 1. Preparation of a toluene solution of 2- acetoxybenzoylchloride of Formula III.

[0078] A reactor was equipped with coolant and dropping funnel and was kept in an inert atmosphere by nitrogen flow. The reactor was connected to a trap containing soda to neutralize acid vapours. 90.9 g of 2-acetoxybenzoic acid of Formula II, 3.8 g of dimethylformamide (DMF) and 632 g of toluene were loaded into the reactor and the temperature was increased to 45±5 °C. Over the period of approximately 60 minutes, by maintaining the temperature of 4515 °C, 78.2 g of thionyl chloride were dripped and subsequently the reaction was kept under stirring for 1.5 hours at the temperature of 4515 °C. At the end of the stirring, the end-of-reaction control was carried out (acetylsalicylic acid residue less than 5%) . 553 ml of toluene were then distilled under vacuum, maintaining the temperature lower than 60 °C. 159 g of toluene were loaded in the reactor and 184 ml of toluene were distilled under vacuum, maintaining the temperature lower than 60 °C. 159 g of toluene were loaded again into the reactor and 184 ml of toluene were distilled under vacuum, maintaining the temperature lower than 60 °C. At the end of the distillation the reactor was brought back to atmospheric pressure and 236 g of toluene were loaded. The toluene solution obtained containing 100.0 g of 2-acetoxybenzoylchloride of Formula III was used as such in the next step.

[0079] Example 2. Preparation of 8- ( 2-hydroxybenzamido ) octanoic acid, compound of Formula V.

[0080] (2a) Preparation of an aqueous solution of the compound of Formula IV-A.

[0081] A reactor was equipped with coolant and dropping funnel and was kept in an inert atmosphere by nitrogen flow. 100.0 g of 8-aminoctanoic acid of Formula IV was loaded into the reactor. A solution with 111.0 g of soda beads (NaOH) and 927.5 g of water was prepared by cooling in order to keep the temperature lower than 40 °C. The soda solution was transferred to the reactor containing 8-aminoctanoic acid, keeping the temperature lower than 25 °C. Stirring was maintained for 20 minutes, at the end of which the solution of the compound of Formula IV-A was cooled to 0°-5 °C.

[0082] (2b) Preparation of an aqueous solution of the compound of Formula V-A. Over the period of approximately 3 hours, maintaining the temperature of 0-5 °C, the toluene solution of 2- acetoxybenzoylchloride of Formula III prepared in Example 1 was added to the reactor containing the aqueous solution of the compound of Formula IV-A. At the end of the addition the reaction was kept under stirring for 1 hour at the temperature of 0°-5 °C, the temperature was then increased to 20-25 °C and the stirring was maintained for another 8 hours. End-of- reaction control was performed ( 2-acetoxybenzoylchloride residue <1.0%) . The stirring was stopped and the two phases were separated. The overlying toluene phase was sent to disposal. The underlying aqueous phase containing the product (aqueous solution of the compound of Formula V-A) was loaded again into the reactor.

[0083] (2c) Preparation of the compound of Formula V.

[0084] A diluted solution of 6% (w / w) hydrochloric acid was prepared by diluting 167.1 g of 37% (w / w) HC1 in 862.0 g of water. Maintaining the temperature T<25 °C, the diluted hydrochloric acid solution thus prepared was slowly dripped into the reactor containing the aqueous solution of the compound of Formula V- A until the pH of 6.010.2 was reached. During the addition the precipitation of the product (compound of Formula V) was observed. When the pH was stable at 6.010.2, stirring was maintained for about 1 hour. The pH was checked again and, if necessary, was brought back in the range 6.010.2. The suspended solid was filtered and the panel was washed twice with 200.0 g of water. The solid was not dried, but left wet. Based on the weight loss, 100.0 g of compound of Formula V was obtained (72% molar yield, informative value) .

[0085] (2d) Purifications of the compound of Formula V.

[0086] In cases where the compound of Formula V obtained from the previous step had a purity of less than 98%, at least one of the following purifications was carried out. Purification 1.

[0087] Maintaining the temperature T<40 °C, a 2 M soda solution (2M NaOH) was prepared by dissolving 32.0 g of soda beads in 385.0 g of water. A suitable reactor was equipped with coolant and dropping funnel, and was kept in an inert atmosphere by nitrogen flow. The wet compound of Formula V obtained from the previous step and the previously prepared 2 M solution of soda were loaded into the reactor, stirring was maintained for about 20 minutes at the temperature of 20°-25 °C. During this time the solid melts. 1.0 g of EDTA (1% w / w) were added to the solution containing the compound of Formula V and soda and stirring was maintained for 20 minutes. The solution was then filtered onto cellulose and the panel was washed with 20.0 g of water. The solution of the compound of Formula V and filtered soda was loaded again into the reactor. A 1.2 M solution of HC1 was prepared by diluting 65.3 g of 37% (w / w) HC1 with 665.0 g of water. The 1.2 M solution of HC1 was slowly dripped into the reactor containing the solution of the compound of Formula V and soda until a pH of 6.010.2 was reached. During the addition the precipitation of the product (compound of Formula V) was observed. When the pH was stable at 6.010.2, stirring was maintained for about 1 hour. The pH was checked again and, if necessary, was brought back in the range 6.010.2. The suspended solid was filtered and the panel was washed 3 times with 100.0 g of water. The solid was not dried, but left wet with water. Based on the weight loss, 90.0 g of compound of Formula V were obtained (purification yield 90 mol % , informative value) . Weight loss (corresponding to wetting water) had to be comprised between 20% and 30%.

[0088] Purification 2.

[0089] A reactor was equipped with coolant and dropping funnel and was kept in an inert atmosphere by nitrogen flow. The wet compound of Formula V obtained from the previous step was loaded into the reactor; if the weight loss was less than 20%, water was loaded into the reactor until the amount of water present was brought back between 20% and 30%. 355.5 g of methanol was loaded into the reactor and the mass was heated to the temperature of 50 °C±3 °C obtaining a complete solution. Stirring was maintained for 20 minutes. Maintaining the temperature of 50 °C±3 °C, over the period of approximately 2 hours, 450.0 g of water was dripped into the reactor; product precipitation was observed during addition. At the end of the addition the suspension was kept under stirring at the temperature of 50 °C±3 °C for at least 30 minutes, then cooled to the temperature of 20°-25 °C and kept under stirring for 2 hours. The product was filtered and the panel was washed twice with 180.0 g of water. The wet solid was dried in an oven at 50 °C under vacuum for 16 hours, obtaining 81.0 g of the compound of Formula V.

[0090] Example 3. Preparation of salcaprozate sodium of Formula I.

[0091] A reactor was equipped with coolant and dropping funnel and was kept in an inert atmosphere by nitrogen flow. 81.0 g of compound of Formula V and 243 ml of absolute ethanol were loaded in the reactor. The reaction mixture was heated to the temperature of 35 °C. A soda solution was prepared by dissolving 11.6 g of soda beads in 40 ml of water. The soda solution thus prepared was dripped into the reactor containing the compound of Formula V and ethanol. Stirring was maintained for 1 hour to obtain a salcaprozate sodium solution of Formula I. The salcaprozate sodium solution of Formula I was microfiltered. Maintaining the temperature of 30°-35 °C, 243 ml of ethanol and subsequently 296 ml of heptane were added to the filtered solution. During this addition the product precipitated. The suspension was cooled to 10 °C and stirring was maintained for 3 hours. The suspended solid was filtered and the panel was washed with 160 ml of heptane. 83.0 g of salcaprozate sodium were obtained.

[0092] Example 4. Preparation of salcaprozate sodium of Formula I.

[0093] In a reactor, 81 g of the compound of Formula V was suspended in 162 g of water, the temperature was stabilized at 20°-25 °C, stirring was started and maintained for half an hour. Maintaining the temperature T<30 °C, over the period of approximately 1 hour, 152 ml of 2M NaOH were dripped until a pH=8.610.1 was obtained. The suspended product dissolved slowly. At the end of the addition, the temperature was brought to 33°±3 °C and stirring was maintained for 30-45 minutes. The solution thus obtained was sent to the spray-dryer with an inlet temperature of 220 °C and an outlet temperature of 112 °C. The sprayed product was recovered from the spray-dryer collection vessel, obtaining 73 g of salcaprozate sodium. Example 5. Preparation of salcaprozate sodium of Formula I.

[0094] In a reactor 83 g of salcaprozate sodium were dissolved with a previously prepared mixture of 373 g of water and 373 g of ethanol. The solution thus obtained was sent to the spraydryer and sprayed with an inlet temperature of 220 °C and an outlet temperature of 112 °C. The sprayed product was recovered from the spray-dryer collection vessel, obtaining 73 g of salcaprozate sodium.

[0095] Example 6. Preparation of salcaprozate sodium of Formula I.

[0096] In a reactor 83 g of salcaprozate sodium were dissolved with a previously prepared mixture of 373 g of water and 373 g of acetone. The solution thus obtained was sent to the spraydryer and sprayed with an inlet temperature of 220 °C and an outlet temperature of 112 °C. The sprayed product was recovered from the spray-dryer collection vessel, obtaining 73 g of salcaprozate sodium.

Claims

CLAIMS1. Process for preparing salcaprozate sodium of FormulaI :Formula I, wherein said process comprises: a) reacting a compound of Formula II:Formula II with a chlorinating agent in a water-immiscible organic solvent to obtain an organic solution of a compound of Formula III:Formula III in said water-immiscible organic solvent; b) reacting a compound of Formula IV:Formula IV with a base in aqueous solution to obtain an aqueous solution of a salt of Formula IV-A:Formula IV-A where M+ is a cation of an alkaline or alkaline-earth metal; c) reacting the organic solution of the compound of Formula III obtained from step a) with the aqueous solution of the compound of Formula IV-A obtained from step b) to obtain a biphasic mixture comprising an organic phase and an aqueous phase, wherein a compound of Formula V-A:Formula V-A is dissolved in the aqueous phase; d) separating the aqueous phase containing the compound of Formula V-A from the organic phase of the biphasic mixture obtained in step c) and adding an acid to the aqueous phase to obtain a compound of Formula V:Formula V e) reacting the compound of Formula V with an inorganic base containing Na+ to obtain salcaprozate sodium of formula (I) •2. Process according to claim 1, wherein in step a) the chlorinating agent is selected from: thionyl chloride (SOC12) , phosphorus trichloride (PC13) , phosphorus pentachloride (PC15) , oxalyl chloride; preferably the chlorinating agent is thionyl chloride.

3. Process according to any one of the preceding claims, wherein in step a) the organic solvent is selected from: a water-immiscible chlorinated solvent, selected for example from methylene chloride, chloroform, carbon tetrachloride, or mixtures thereof; a water-immiscible ether, for example t- butyl methyl ether; an aromatic water-immiscible hydrocarbon, preferably selected from toluene, xylene, benzene; more preferably it is toluene.

4. Process according to any one of the preceding claims, wherein in step a) a catalyst is added, preferably selected from: dimethylformamide (DMF) , pyridine, N-ethyl diisopropylamine (DIPEA) , hexamethylenediamine (HMDA) ; more preferably the catalyst is DMF.

5. Process according to any one of the preceding claims, wherein in step a) the molar ratio of chlorinating agent to compound of Formula II is comprised between 1.10 and 1.50, preferably between 1.20 and 1.40.

6. Process according to any one of the preceding claims, wherein in step b) the base in aqueous solution is a hydroxide of an alkaline or alkaline-earth metal, preferably a hydroxide of an alkaline metal, more preferably is sodium hydroxide (NaOH) .

7. Process according to any one of the preceding claims, wherein in step c) the organic solution of the compound of Formula III prepared in step a) is mixed with the aqueous solution of the compound IV-A prepared in step b) at a temperature comprised between -5 °C and 10 °C, preferably between 0 °C and 5 °C.

8. Process according to any one of the preceding claims, wherein in step c) the organic solution of the compound of Formula III prepared in step a) is added to the aqueous solution of the compound IV-A prepared in step b) by dropping, with a dropping time comprised between 2 and 4 hours, preferably between 2.5 and 3.5 hours.

9. Process according to any one of the preceding claims, wherein in step c) the reaction is carried out by stirring for a time comprised between 6 and 10 hours, preferably between 7 and 9 hours, at a temperature between 15 °C and 30 °C, preferably between 20 °C and 25 °C.

10. Process according to any one of the preceding claims, wherein in step d) the acid is added in an amount so as to obtain a pH comprised between 5.8 and 6.2, preferably between 5.9 and 6.1.

11. Process according to any one of the preceding claims, wherein, after step d) at least one step d' ) of purifying the compound of Formula V is carried out.

12. Process according to claim 11, wherein the purifying step d' ) comprises: (i) adding to the compound of Formula V obtained from step d) a base so as to obtain a solution of a carboxylate salt of the compound of Formula V; (ii) adding to said solution a complexing agent which is capable of complexing metal ions present as impurities with the formation of a suspension; (iii) filtering the suspension thus obtained so as to separate complexed metal ions from the solution of the compound of Formula V in the form of carboxylate salt; (iv) acidifying the solution of the compound of Formula V in the form of carboxylate salt so as to precipitate the compound of Formula V which is then separated.

13. Process according to claim 12, wherein the complexing agent added in step (ii) is selected from: ethylenediaminetetraacetic acid (EDTA) , ascorbic acid, NaHSO3; preferably the complexing agent is EDTA.

14. Process according to claim 11, wherein the purifying step d' ) comprises: (v) dissolving the compound of Formula V obtained from step d) in a polar organic solvent selected from: R-OH alcohols where R is a straight or branched Ci-Cg alkyl, preferably straight, more preferably the alcohol is methanol; ketones of general formula R1-CO-R2, wherein the groups R1 and R2, equal to or different from each other, are straight or branched Ci-Cg alkyls, preferably R1 is equal to R2 , more preferably the ketone is acetone; or mixtures thereof; (vi) adding water to the solution of the compound of Formula V obtained from step (v) so as to precipitate the compound of Formula V which is then separated.

15. Process according to claim 14, wherein in step (vi) water is added in an amount so as to obtain a weight / weight ratio of water to compound of Formula V from 4.3 to 5.4, more preferably 4.6 to 5.3, even more preferably 4.8 to 5.2.

16. Process according to any one of claims 11 to 15, wherein the purification d' ) of the compound of Formula V is obtained by a first purifying step according to steps (i)- (iv) , which is followed by a second purifying step according to steps ( v) - ( vi ) .

17. Process according to any one of the preceding claims, wherein in step e) the inorganic base containing Na+ is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, preferably it is sodium hydroxide.

18. Process according to any one of the preceding claims, wherein in step e) the compound of Formula V is dissolved in a polar organic solvent selected from: R-OH alcohols, where R is a straight or branched Ci-Cg alkyl group, preferably straight, more preferably the alcohol is ethanol; ketones of general formula R1-CO-R2, wherein the groups R1 and R2, equal to or different from each other, are straight or branched Ci- Cg alkyl groups, preferably R1 is equal to R2, more preferably the ketone is acetone; ethers of general formula R3-O-R4, wherein the groups R3 and R4, equal to or different from each other, are straight or branched Ci-Cg alkyl groups; or mixtures thereof .

19. Process according to any one of the preceding claims, wherein in step e) an apolar organic solvent selected from straight or branched Cg-Cg alkanes, preferably straight, in particular heptane, is added to the solution of the compound of Formula V and the inorganic base containing Na+ in a polar organic solvent.

20. Process according to any one of the preceding claims, wherein the salcaprozate sodium in the form of a solution in water and / or in organic solvent obtained from step e) is subjected to a spray drying process.

Images