EP4277899A1

EP4277899A1 - Process for the synthesis of imepitoin

Info

Publication number: EP4277899A1
Application number: EP22703447.7A
Authority: EP
Inventors: Martino Veronese; Alessandro Barozza; Piergiorgio Bettoni; Jacopo Roletto; Paolo Paissoni
Original assignee: Procos SpA
Current assignee: Procos SpA
Priority date: 2021-01-18
Filing date: 2022-01-17
Publication date: 2023-11-22
Also published as: IT202100000782A1; WO2022153263A1

Abstract

Disclosed is a process for the synthesis of imepitoin of formula (I) by reacting 4- chloroaniline, chloroacetic acid and urea in the presence of an apolar or weakly polar aprotic solvent such as xylene, and then reacting the resulting 1-(4- chlorophenyl)imidazolidine-2, 4-dione (II) with morpholine in the presence of morpholine hydrochloride. Crystallisation from dimethyl sulphoxide and methanol provides pure imepitoin (I). The process is cheaper and more easily industrially scalable than the known procedures, thus enabling imepitoin to be produced with high yields and limited costs.

Description

PROCESS FOR THE SYNTHESIS OF IMEPITOIN

FIELD OF INVENTION

The present invention relates to a process for the preparation of imepitoin (I) by means of efficient preparation of its intermediate l-(4-chlorophenyl)imidazolidine-2,4- dione (II) followed by condensation with morpholine in the presence of morpholine hydrochloride and final recrystallisation from dimethylsulphoxide and methanol.

BACKGROUND TO THE INVENTION

Imepitoin is an anticonvulsant used in veterinary medicine to treat canine epilepsy. The medicament also has tranquillising effects.

Imepitoin acts as a low-affinity partial agonist of the benzodiazepine site of the GABAA receptor. It is the first partial agonist approved for the treatment of epilepsy. The medicament also blocks the voltage-dependent calcium channels to a dose-dependent extent.

The known synthesis strategies for the preparation of imepitoin describe its preparation from the intermediate l-(4-chlorophenyl)imidazolidine-2, 4-dione (II) by condensation with morpholine.

DE 19532668A1 describes the manufacturing process of imepitoin by reaction between l-(4-chlorophenyl)imidazolidine-2, 4-dione (II) and morpholine, used as solvent/reagent, with the addition of an acid catalyst such as -toluenesulphonic acid, at the reflux temperature of morpholine (129°C).

To force the conversion to acceptable values (as will be deduced from the general method, the conversion is about 60%), the water formed during the reaction is removed with a Soxhlet apparatus, the thimble of which is filled with desiccant material (such as sodium sulphate, magnesium sulphate, NaOH, KOH, zeolites or similar).

The proposed isolation procedure then requires the amine to be evaporated and the imepitoin obtained to be recovered by extraction in acetone and then crystallised from n- propanol.

From an industrial point of view this method is difficult to apply, because a Soxhlet apparatus is not generally used, nor is it cheap. Moreover, evaporating the final reaction mixture until dryness is not an industrially simple operation. Moreover, considering the poor solubility of imepitoin in both acetone and n-propanol, very large solvent volumes are required to isolate the product.

J. Med. Chem. 2006, 49, 6, 1855-1866 cites the preparation of imepitoin by a similar reaction, using a very large amount of morpholine compared with the starting substrate, and using the hydrochloride of the amine (morpholine) as catalyst. In this case, desiccants are not used, and the reaction is conducted at 110-140°C. The product is isolated by cooling the reaction mixture and recovering the resulting solid by filtration. The solid is then recrystallised from alcohols.

Once again, large volumes of alcohols are required to recrystallise the product.

Both cited procedures use the same starting substrate (II), although its preparation is not directly cited.

J. Prakt. Chem. 1926, 113, 233-267 describes the preparation of phenylhydantoin in two steps, the first involving synthesis of aminophenylacetic acid and the second involving formation of the hydantoin ring by the action of potassium cyanate.

Said general procedure for formation of the hydantoin ring is used in EP 116825 for the synthesis of (II) from p-CJPhNHCHzCOOH. As the product used in the synthesis needs to be isolated, the process is not very advantageous.

Drug Research, Volume 1, Issue 1, 189-96, 1968, describes the preparation of (II) from jg-chlorophenylurea and from chloroacetic acid ethyl ester. By reacting the two compounds in ethanol at reflux in the presence of sodium ethoxide, (II) is obtained with a yield of 70%.

Unfortunately, despite the high yield of the preparation, the two starting compounds are already more synthetically advanced than the raw materials cited in other publications, and the cost of their preparation would make the process uneconomical.

The Journal of Pharmaceutical Sciences, Volume 62, Issue 2, pages 340-1, reports the preparation of (II), again starting with the asymmetrical urea y?-chlorophenylurea, and using glyoxal as second reagent. The yield reported for compound (II) is 30%.

Once again, starting with a product whose preparation requires at least one synthesis step (p-chloro phenyl urea) and gives a total yield of 30% makes the process uneconomical.

Khimiya Geterotsiklicheskikh Soedinenii, Issue 1, pages 87-9 (1978) and Russian Journal of Organic Chemistry, Volume 47, Issue 6, pages 960-963 (2011) cite the preparation of (II) from p-chloroaniline, chloroacetic acid and urea, under heating and in the absence of solvent. In both publications the yields are fairly high (53% and 62% respectively).

The proposed method has the undeniable advantage of starting from inexpensive substances but, being conducted in the total absence of solvent, is still affected by an intrinsic difficulty of industrial scalability, because loading solids into a reactor and heating them up to melting point in the absence of stirring is a critical operation. Moreover, a footnote to the most recent reference states that at the end of the reaction, at 140°C, the mixture of molten compounds solidifies, and in order to empty the reactor the solid must be dispersed in water and methanol, an operation which is difficult to perform without stirring.

Tetrahedron Letters, Volume 52, Issue 46, pages 6148-6151 (2011), describes the synthesis of substituted hydantoins from an N-cyano precursor, by a dialkyl phosphate.

Although the synthesis method is fairly efficient (yield 85%), the cost of the reagents used makes the process not cost-effective.

DESCRIPTION OF THE INVENTION

It has now surprisingly been found that intermediate (II) can be advantageously synthesised by a readily industrially scalable method by suspending p-chloroaniline in apolar or weakly polar aprotic solvents, adding chloroacetic acid and solid urea and heating the system at temperatures of at least 80°C, typically at a temperature ranging between 80°C and the boiling point of the solvent, for 1-8 hours, and then at the boiling point of the solvent for 1-8 hours. The procedure is conducted in a stirred reactor without the occurrence of critical events modifying the mass that could block the stirring system. The chloroacetic acid and solid-state urea are preferably added in portions, with the addition rate regulated so as to minimise rapid variations in the viscosity of the mass maintained under stirring. The order of addition of the solid species is not critical, and can be varied without prejudicing the end result of the reaction.

Apolar aprotic or weakly polar aprotic solvents proved to be excellent means for dispersing the various solid species, overcoming the scalability limits of some of the methods cited in the literature. Examples of said solvents are xylene, toluene, chlorobenzene and aliphatic hydrocarbons. A preferred solvent is a xylene, either pure or as a mixture of isomers.

It has also been found that if the reaction between (II) and morpholine is conducted in the presence of morpholine hydrochloride, morpholine consumption is considerably reduced without the need to use desiccant systems or reagents.

It has also been found that the final crystallisation of imepitoin can be conducted by dissolving the crude product in dimethylsulphoxide under heating (typically 10 volumes) and, after cooling by adding methanol, leaving the end product to crystallise. In this way the large volumes of alcohols required for crystallisation of the final imepitoin (e.g. 50-60 volumes) can be drastically reduced.

The process according to the invention for synthesis of imepitoin from simple substances such as p-chloroaniline, chloroacetic acid, urea and morpholine allows industrialisation at a considerably lower cost than other known procedures.

DETAILED DESCRIPTION OF THE INVENTION

The preparation of (II) is efficiently conducted by suspending -chloroanilinc (1 eq) at room temperature under stirring in 1-10 volumes, preferably 3 volumes, of technical xylene (mixture of isomers), adding chloroacetic acid (1-3 equivalents, preferably 1 equivalent) in portions, and then adding urea (1-3 equivalents, preferably 1 equivalent) in portions, subsequently heating the stirred system to 80°C, and after 1-8 hours at said temperature, preferably 2 hours, further heating to 125°C for another 1-8 hours, preferably 2 hours.

The system is left to cool, and then diluted with water. The pH is adjusted to 11 -

13, preferably 11.5-12.5, by adding cone. NaOH. The suspended solid (by-product) is eliminated by filtration, and the organic phase of the clear biphasic mixture is discarded. The aqueous phase is washed 3 times with toluene and acidified to pH 9-11, preferably

9.5-10.5, by adding concentrated hydrochloric acid.

When solid formation is noted, the system is left under stirring at room temperature for 30-240 minutes, preferably 60 minutes, and the solid is isolated by filtration.

The panel is washed in sequence with water and methanol, and the solid is dried under vacuum at the temperature of 50°C to a constant weight. The typical isolation yield (II) ranges between 25% and 45%.

The preparation of imepitoin (I) is efficiently conducted by suspending product (II), obtained as described above, in a solution of 2-10 volumes, preferably 2.5 volumes, of morpholine and 1-5 equivalents, preferably 2 equivalents, of morpholine hydrochloride, and heating the system to reflux temperature for 12-72 hours, preferably 24 hours.

At the end of the reaction the heterogeneous mass is cooled, and 3-15 volumes of methanol, preferably 6.5 volumes, are added. The solid formed is isolated by filtration, washing the panel in sequence with methanol, water and methanol. The crude imepitoin (I) yield ranges between 60% and 70%.

The wet solid (crude imepitoin) is dissolved under heating in dimethyl sulphoxide (5-20 volumes, preferably 10) and left to crystallise by subsequent cooling. 20 volumes of methanol are added at room temperature and the solid is isolated by filtration, washing the panel with methanol. The wet solid is dried under vacuum at 50°C to a constant weight. The resulting polymorph is a further object of the invention, and is characterised by powder X-ray diffractogram, acquired under the conditions shown in Figure 1 and summarised in Table 1 below:

Conditions: PAN Analytical X’Pert Pro 45 KVolt, 40 mA, PAN Analytical XRD X’Pert tube - LFF (Long fine focusing). Radiation: Cu target with 2 Beryllium windows. Range (2Theta): 2° - 50°. Table 1

PXRD Peak List

The invention will now be illustrated in detail by the following examples.

Example 1 : Synthesis of l-(4-chlorophenyl)imidazolidine-2, 4-dione (II) 60 ml of xylene (mixture of isomers) is loaded into a mechanically stirred threenecked reaction flask, followed by 20 g of p-chloroaniline (157 mmols). Leaving the system under stirring, 14.8 g of chloroacetic acid (157 mmols) is added in portions followed by 9.4 g of urea (157 mmols), again added in portions. The system is then heated to 80°C, and said temperature is maintained for two hours. After that time, the system is further heated to 125°C for 2 hours.

The system is then cooled, and at 25°C, 100 mL of water is loaded. The pH is adjusted to 12 by adding cone. NaOH (about 33.6 g at 30%, about 252 mmols). The system is left under stirring for about 1 hour, and the formed solid is then eliminated by filtration. The organic phase of the clear biphasic mixture is discarded, and the aqueous phase is washed 3 times with toluene (40 ml each time, 120 mL in total).

The aqueous phase is acidified with cone. HC1 to pH 10. The suspension is left under stirring for 1 hour at room temperature, and the solid is then isolated by filtration. The filter panel is washed with 300 ml of water, and then with 60 ml of methanol. The wet product is transferred to an oven and dried under vacuum at the temperature of 50°C to a constant weight. 6.9 g of (II) is obtained, with a yield of 20.9%.

^XH NMR (400 MHz, DMSO-t/e) 8 4.44 (s, 2H), 7.43 (m, 2H), 7.63 (m, 2H), 11.24 (s, 1H).

The purity of the product is determined by HPLC (XBridge Cl 8 column, 150 mm x 4.6 mm, 3.5 pm; Phase A 10 mM ammonium acetate pH 6.5, Phase B: acetonitrile; gradient from A 95%; Flow rate 1 mL/min; 260 nm) and is greater than 99%.

Example 2: Synthesis of imepitoin (I)

17.2 g of morpholine and 8.1 g of morpholine hydrochloride (66 mmols) are loaded into a mechanically stirred 3-necked reaction flask. 6.9 g of l-(4- chlorophenyl)imidazolidine-2, 4-dione (II) is then loaded under stirring. The system is then heated at reflux for 24 h. After that time the system is cooled slowly to 35°C, and 46 mL of methanol is added. The system is left under stirring at room temperature for 30 minutes, and the solid is then isolated by filtration. The filter panel is washed in sequence with 10 mL of methanol, 31 mL of water and a further 10 ml of methanol.

The wet solid is discharged from the filter and loaded into a mechanically stirred three-necked reaction flask. 58 ml of dimethylsulphoxide is added, and the system is heated to 105°C, dissolving the solid. The system is then cooled slowly to 25°C, and 116 mL of methanol is added drop by drop. The system is left under stirring at room temperature for 1 hour, and the solid is isolated by filtration, washing the panel twice with methanol (30 mL each time, total 60 ml).

The resulting solid is transferred to a vacuum oven and dried at 50°C to a constant weight. 4.8 g of pure imepitoin (I) is obtained, with a yield of 52.6% compared with (II).

^!H NMR (400 MHz, DMSO-^) 8 3.44 (m, 2H), 3.67 (m, 4H), 3.72 (m, 2H), 4.73 (s, 2H), 7.39 (m, 2H), 7.68 (m, 2H)

The purity of the product is determined by HPLC (XBridge Cl 8 column, 150 mm x 4.6 mm, 3.5 pm; Phase A 10 mM ammonium acetate pH 6.5, Phase B (acetonitrile; gradient from A 95%; Flow rate 1 mL/min; X 260 nm), and is greater than 99.9%. The polymorphic form conforms to the PXRD pattern shown in Figure 1.

Claims

9 CLAIMS

1. A process for the preparation of imepitoin, comprising: a) adding chloroacetic acid to a suspension of p-chloroaniline in an apolar or weakly polar aprotic solvent; b) adding solid urea and heating to a temperature ranging between 80°C and the boiling point of the solvent to give l-(4-chlorophenyl)imidazolidine-2 ,4- dione (II); c) reacting l-(4-chlorophenyl)imidazolidine-2, 4-dione (II) with morpholine in the presence of morpholine hydrochloride and crystallising the final product.

2. The process according to claim 1 wherein the non-polar or slightly polar aprotic solvent is selected from xylene, toluene, chlorobenzene and aliphatic hydrocarbons.

3. The process according to claim 2 wherein the solvent is xylene.

4. The process according to claim 1 , 2 or 3 wherein crystallisation is carried out by adding methanol to a solution of crude imepitoin in dimethyl sulphoxide.

5. The process according to one or more of claims 1 to 4 wherein step a) is carried out at room temperature.

6. The process according to one or more of claims 1 to 5 wherein the addition of chloroacetic acid and the addition of urea are carried out in portions.

7. A process for the preparation of l-(4-chlorophenyl)imidazolidine-2, 4-dione (II) comprising: a) adding chloroacetic acid to a suspension of /2-chloroaniline in an apolar or weakly polar aprotic solvent; b) adding solid urea and heating to a temperature ranging between 80°C and the boiling point of the solvent.

8. The process according to claim 7 wherein the apolar or weakly polar aprotic solvent is selected from xylene, toluene, chlorobenzene and aliphatic hydrocarbons.

9. The process according to claim 8 wherein the solvent is xylene.

10. A process according to one or more of claims 7 to 9 wherein step a) is carried out at room temperature and wherein the addition of chloroacetic acid and the addition of urea are carried out in portions.

11. A polymorph of imepitoin having the following XRPD peaks at the Cu wavelength