FIELD OF INVENTION

The invention relates to a new process for preparing 2H-l,3-benzoxazine-2,4(3H)- dione, also known as Carsalam.

STATE OF THE ART 2H-l,3-Benzoxazine-2,4(3H)-dione, also known as Carsalam, of formula (I), is known as a non-steroidal analgesic (cf. Merck Index, XII edition, n.1915). For example, patent application GB950065A filed on January 25, 1960 claims a pharmaceutical composition comprising Carsalam and its use as an analgesic or anxiolytic.

Carsalam is also described in US 3,409,615 filed on October 1, 1965, which discloses a process for preparing Carsalam comprising the reaction of salicylamide, or 2- hydroxybenzamide, of formula (II) with an ester alkyl of chloroformic acid in an aqueous solution and in presence of an inorganic base, for example potassium carbonate or sodium hydroxide. This process avoids organic solvents, such as acetonitrile as used by Shapiro et al. in J. Am. Chem. Soc. 79, 1957, 2811-2814. Acetonitrile is a solvent, being, according to the ICH Guidelines (ICH Harmonised Tripartite Guideline - Impurities: Guideline for Solvents Q3C(R5)), part of class 2 solvents, which are toxic solvents that should be avoided.

Processes disclosed in US 3,409,615 and by Shapiro et al. make use of ethyl chloroformate. The use of said compound requires high precautions and controls, since ethyl chloroformate is corrosive and toxic by inhalation.

Thus, there remains a need for an improved process for the preparation of 2H-1,3- benzoxazine-2,4(3H)-dione of formula (I), which overcomes all the drawbacks deriving from the use of ethyl chloroformate and which can be easily used on industrial scale.

The new process for obtaining 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I) should not only avoid the use of ethyl chloroformate, but also of toxic organic solvents. In addition, this new process should employ efficient, cost-effective and operationally simple reaction conditions in order to obtain 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I) in an advantageous way, in particular on an industrial scale, as well as in high yields and high purity.

SUMMARY OF THE INVENTION

Object of the invention is a process for obtaining 2H-l,3-benzoxazine-2,4(3H)- dione, also known as Carsalam, of formula (I) comprising: reacting salicylamide of formula (II), or a salt thereof, with a dialkyl carbonate of formula (III) in presence of a base.

This process not only avoids the use of ethyl chloroformate, thus of a toxic reagent harmful to the environment, but also allows to obtain 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I) in safe conditions and with a high degree of purity, in order to meet the regulatory requirements for APIs (Active Pharmaceutical Ingredients).

DETAILED DESCRIPTION OF THE INVENTION

Object of the invention is a process for obtaining 2H-l,3-benzoxazine-2,4(3H)- dione of formula (I), comprising:

- reacting salicylamide of formula (II), or a salt thereof,

- with a dialkyl carbonate of formula (III)

O

^R O ^A O ^r '

(III) wherein R and R', which can be the same or different, are a C1-C6 alkyl group; in presence of a base.

According to the present invention, "comprising" herein means that additional steps may be taken in the processing, which do not substantially change the product produced by the reaction. The term comprising encompasses the terms "consisting of' and "consisting essentially of'.

Salicylamide of formula (II), or a salt thereof, is a well-known compound and is commercially available or can be prepared by methods known to a person skilled in the art.

A salt of salicylamide of formula (II) comprises salts derived from an appropriate base, for instance alkaline metal salts (such as sodium or potassium), alkaline earth metal salts (such as calcium or magnesium), ammonium or NRV, wherein R ¹ is a C1-C4 alkyl group, such as methyl, ethyl, propyl, isopropyl or butyl, isobutyl or tert- butyl.

A dialkyl carbonate of formula (III) is a well-known compound and is commercially available or can be prepared by methods well known to a person skilled in the art. Processes for preparing a dialkyl carbonate of formula (III) are for instance described in EP 0 366 177, EP 0460 735, EP 0 742 198, US 5,591,883, US 5,902,894, or in US 6,392,078.

The C1-C6 alkyl group may be a linear, branched or cyclic hydrocarbon chain radical, consisting of carbon and hydrogen atoms, having from one to six carbon atoms. Examples are methyl, ethyl, propyl, isopropyl or butyl, isobutyl, /c/7- butyl, or cyclohexyl.

In a preferred embodiment, the C1-C6 alkyl group is a C1-C4 alkyl group, such as methyl, ethyl, propyl, isopropyl or butyl, isobutyl or /er/-butyl.

The C1-C6 alkyl group can be optionally substituted by one or more halogen atoms, for example by chlorine or fluorine.

A base can be an inorganic base or an organic base.

The inorganic base is typically an alkali or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide; or an alkaline or alkaline earth metal carbonate, such as sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate; or a C1-C6 alcoholate, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert- butoxide or potassium /c/V-butoxide; or an alkali metal hydride, typically sodium hydride or potassium hydride.

The C1-C6 alcoholate may be a linear or branched C1-C6 alkyl alcohol anion, wherein C1-C6 alkyl is as defined herein. Examples are alkali or alkaline earth metal C1-C6 alcoholates, such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium /c/V-butoxide or potassium /er/-but oxide.

In a preferred embodiment of the invention, an inorganic base is sodium or potassium methoxide, or sodium or potassium ethoxide, or sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate.

An organic base is typically an aliphatic or heteroaromatic tertiary amine, such as triethylamine, tri-n-butylamine, methyl-piperidine, ethyl-piperidine or pyridine.

The reaction of salicylamide of formula (II), or a salt thereof, with a dialkyl carbonate of formula (III) can be carried out in absence or in presence of a solvent.

In one embodiment of the invention, the reaction of salicylamide of formula (II), or a salt thereof, with a dialkyl carbonate of formula (III) can be carried out in presence of a solvent.

The solvent can be, for example, an aprotic polar solvent, such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile or dimethylsulfoxide; or an acyclic or cyclic ether, such as methyl /c/V-butyl ether, tetrahydrofuran or dioxane; a chlorinated solvent, such as dichloromethane, dichloroethane, chloroform or chlorobenzene; an apolar aprotic solvent, typically toluene; a polar protic solvent, typically a linear or branched Ci-Cs alcohol, such as a C1-C5 alcohol, in particular methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol; water; or a mixture of two or more, preferably two or three, of said solvents.

In a preferred embodiment, the solvent is ethanol, n-propanol, isopropanol, n- butanol or isobutanol. In a particularly preferred embodiment, the solvent is n-butanol or ethanol, more preferably the solvent is n-butanol.

In one embodiment, the reaction of salicylamide of formula (II), or of a salt thereof, as defined above, with a dialkyl carbonate of formula (III), as defined above, can be carried out at a temperature between about 0°C and the reflux temperature of the reaction mixture, preferably at a temperature between about 0°C and about 150°C. More preferably, the reaction can be carried out at temperatures equal to or below about 140°C, e.g. at about 130°C, at about 120°C, at about 110°C, at about 100°C, at about 90°C, at about 80°C, at about 70°C, at about 60°C, at about 50°C, at about 40°C or at about room temperature.

In one embodiment, the reaction of salicylamide of formula (II), or of a salt thereof, as defined above, with a dialkyl carbonate of formula (III), as defined above, can be advantageously carried out using about 1 to about 20 moles of dialkyl carbonate of formula (III) with respect to one mole of salicylamide of formula (II), for example about 1 to about 16 moles of dialkyl carbonate of formula (III) with respect to one mole of salicylamide of formula (II).

In a preferred embodiment, the reaction of salicylamide of formula (II), or of a salt thereof, as defined above, with a dialkyl carbonate of formula (III), as defined above, can be advantageously carried out preferably from about 1 to about 15 moles, for instance from about 1.5 to about 4 moles or from about 1.5 to about 12 moles, more preferably about 2.0, about 2.5, about 3.0, about 3.3, about 3.5, about 4.0, about 4.5, about 5.0 moles, about 7.0 moles, about 9.0 moles, or about 10 moles of dialkyl carbonate of formula (III) with respect to one mole of salicylamide of formula (II).

In a further embodiment, the reaction of salicylamide of formula (II), or of a salt thereof, as defined above, with a dialkyl carbonate of formula (III), as defined above, can be carried out in absence of any further solvent using about 1 to about 100 moles of dialkyl carbonate of formula (III) with respect to one mole of salicylamide of formula (II), for example about 1 to about 15 moles, about 1 to about 25 moles, about 1 to about 40 moles, or about 1 to about 75 moles of dialkyl carbonate of formula (III) with respect to one mole of salicylamide of formula (II).

The reaction of salicylamide of formula (II), or of a salt thereof, as defined above, with a dialkyl carbonate of formula (III), as defined above, can be advantageously carried out using about 0.8 to about 3 moles of the base with respect to one mole of salicylamide of formula (II), preferably from about 0.9 to about 2.5 moles, more preferably between about 1.0 and about 2.1 moles, for example at about 1.1, about 1.2, about 1.3, about 1.5, about 1.7, about 1.9 or about 2.0 moles of the base with respect to one mole of salicylamide of formula (II).

In a preferred embodiment, the reaction of salicylamide of formula (II), or of a salt thereof, as defined above, with a dialkyl carbonate of formula (III), as defined above, can be advantageously carried out within about 10 minutes to about 96 hours, for example within about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 12 hours, about 24 hours, about 36 hours or about 48 hours.

2H-l,3-benzoxazine-2,4(3H)-dione of formula (I) obtained according to the process described above can be isolated according to known techniques, such as by extraction and concentration to dryness.

Additional known techniques for isolating 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I) may comprise steps of filtration or centrifugation, optionally followed by drying under vacuum.

In one embodiment, the product can be isolated by acidifying the reaction mixture, typically adjusting the reaction mixture with an acid to a pH value of about 1 to about 6, for example to a pH value of about 4, about 5 or about 6. The acid can be a strong protic acid, typically a hydrohalic acid, preferably hydrochloric acid, sulphuric acid or a sulphonic acid, preferably p-toluenesulfonic acid, or a C1-C4 carboxylic acid, wherein the C1-C4 alkyl group can be linear or branched, and wherein the hydrogen atoms may be optionally replaced by one or more halogen atoms, preferably from one to three chlorine or fluorine atoms.

Examples of a C1-C4 carboxylic acid are formic acid, acetic acid or trifluoroacetic acid.

In a preferred embodiment, the acid is hydrochloric acid or acetic acid.

In a preferred embodiment, the product is isolated by filtration, optionally rinsed with a solvent, and then dried under vacuum. For example, drying can be carried out at a temperature of about 0°C to about 100°C, for example at about 30°C, about 40°C, about 45°C, about 50°C or about 60°C.

2H-l,3-Benzoxazine-2,4(3H)-dione of formula (I) obtained by the herein described process has a chemical purity (Area %), evaluated by HPLC at 245 nm, of 98% or higher, preferably of 99.8% or higher, such as 99.95%, 99.98% 99.99% or 100.0%.

In addition, the inventors found that 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I) obtained by the process of the present invention has a content of impurities of formula (IV) or formula (V) lower than 0.1%, preferably lower than 0.05%, such as 0.03%, 0.01%, 0.005%,

0.001% or 0.0005%, wherein the R group is as defined above. Impurities of formula (IV) or of formula (V) wherein R is as defined above, result to be intermediates of the reaction of salicylamide of formula (II) with dialkyl carbonate of formula (III).

The impurity of formula (V) as defined above, wherein R is a methyl group, is a new compound and represents a further object of this invention.

2H-l,3-Benzoxazine-2,4(3H)-dione of formula (I) obtained by the process of the present invention has a purity to meet the regulatory requirements required for Active Pharmaceutical Ingredients (APIs).

According to a further aspect of the invention, 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I) can be used as a reaction intermediate, for instance the compound of formula (I) can be converted into the compound of formula (VI)

(VI), and, if desired, the compound of formula (VI) can be converted into a pharmaceutically acceptable salt thereof, such as the sodium or potassium salt.

A further object of the invention is the use of 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I), as defined above, to obtain N-(8-[2-hydroxybenzoyl]amino) octanoic acid of formula (VI), or a pharmaceutically acceptable salt thereof.

A further object of the invention is a process for the preparation of 2H-1,3- benzoxazine-2,4(3H)-dione of formula (I), as defined above, to obtain N-(8-[2- hydroxybenzoyljamino) octanoic acid of formula (VI), or a pharmaceutically acceptable salt thereof.

For example, 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I) obtained according to the process of the present invention can be converted into N-(8-[2- hydroxybenzoyljamino) octanoic acid of formula (VI), as defined above, by reaction with a 8-halo-octanoic acid, such as 8-bromo-octanoic acid or 8-chloro-octanoic acid, and, if desired, converting the obtained N-(8-[2-hydroxybenzoyl]amino) octanoic acid of formula (VI) into its pharmaceutically acceptable salt. The 8-halo-octanoic acid, e.g. 8-bromo- octanoic acid or 8-chloro-octanoic acid, can be optionally protected with protecting groups of the carboxylic acid according to well-known methods in art, for example as described in Greene and Wuts (Greene, T.W.; Wuts, P.G.M. "Protective Groups in Organic Synthesis," John Wiley & Sons Inc., 1999). An example of a protective group of the carboxylic acid can be a C1-C6 alkyl ester, wherein the C1-C6 alkyl group is as defined above.

In particular, the conversion of 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I) into N-(8-[2-hydroxybenzoyl]amino) octanoic acid of formula (VI), or in its pharmaceutically acceptable salt, can be carried out according to procedures as described in the patent applications WO 2001/70219, WO 2008/028859 or CN104974060.

The conversion of N-(8-[2-hydroxybenzoyl]amino) octanoic acid of formula (VI) into its pharmaceutically acceptable salt, in particular into the sodium salt, can be carried out in a solvent, for example in alcohol or water, or in a mixture of solvents.

The following examples further illustrate the invention.

Example 1. Preparation of 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I)

40 mL of n-butanol, 8.0 g (146 mmol) of sodium methoxide and 10.0 g (72.9 mmol) of salicylamide of formula (II) are added under nitrogen atmosphere and at room temperature into a 250 mL 4-neck flask equipped with a mechanical stirrer. The mixture is then heated to 80°C and 20 mL (238 mmol) of dimethyl carbonate of formula (III) are added. After 1 hour at 80°C, the reaction mixture is cooled down to 0°C and 70 mL of a 2 M aqueous solution of hydrochloric acid (HC1) are added bringing the pH of the reaction mixture to about 5. The suspension is stirred at 0°C for a further hour, then the solid is filtered off on a Buchner filter and washed with n-butanol and water providing 9.5 g of 2H- l,3-benzoxazine-2,4(3H)-dione, or Carsalam, of formula (I) as a white solid with an HPLC purity of 99.95% measured at 245 nm and with a yield of 80%. ¹ H-NMR (300 MHz, DMSO-de) d: 12.02 (bs, 1H); 7.91 (d, J= 12.9 Hz, 1H), 7.77 (t, J= 6.0 Hz, 1H), 7.41-7.36 (m, 2H).

Example 2. Preparation of 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I)

200 mL of n-butanol, 23.6 g (437.5 mmol) of sodium methoxide and 50.0 g (364.6 mmol) of salicylamide of formula (II) are added under nitrogen atmosphere and at room temperature in a 4-flask 500 mL reactor equipped with a mechanical stirrer. The mixture is then heated to 60°C and 100 mL (2182 mmol) of dimethyl carbonate of formula (III) are added within 40 minutes. After 24 hours at 60°C, 30 mL (524.6 mmol) of acetic acid are added within 20 minutes bringing the pH to about 4/5. The suspension is then heated to 80°C for one hour, then cooled down to 25°C and 150 mL of water are added. The suspension is stirred for one hour, then the solid is filtered off on a Buchner filter and washed with n-butanol and water providing 50.1 g of 2H-l,3-benzoxazine-2,4(3H)-dione, or Carsalam, of formula (I) as a white solid with an HPLC purity of 99.99% measured at 245 nm and with a yield of 84%. ¾-NMR (300 MHz, DMSO-de) d: 12.02 (bs, 1H); 7.91 (d, 7=12.9 Hz, 1H), 7.77 (t, 7=6.0 Hz, 1H), 7.41-7.36 (m, 2H).

Example 3. Preparation of 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I)

50.0 g (147 mmol) sodium ethoxide 20% ethanol and 10.0 g (72.9 mmol) of salicylamide of formula (II) are added under nitrogen atmosphere and at room temperature in a 250 mL 4-neck flask equipped with a mechanical stirrer. The mixture is then heated to 70°C and 20 mL (238 mmol) of dimethyl carbonate of formula (III) are added. After 1.5 hours at 70°C the suspension is cooled down to 0°C and 60 mL of a 5 M aqueous solution of ammonium chloride (MLCl) are added followed by a 2 M hydrochloric acid (HC1) solution until the reaction mixture is brought to a pH of about 6. The suspension is then stirred for an hour at 0°C, after which the solid is filtered off on a Buchner filter and washed with ethanol and water providing 9.5 g of 2H-l,3-benzoxazine-2,4(3H)-dione, or Carsalam, of formula (I) as a white solid with an HPLC purity of 99.8% measured at 245 nm and with a yield of 80%. ¾-NMR (300 MHz, DMSO-de) d: 12.02 (bs, 1H); 7.91 (d, 7=12.9 Hz, 1H), 7.77 (t, 7=6.0 Hz, 1H), 7.41-7.36 (m, 2H).

Example 4. Preparation of 2H-l,3-benzoxazine-2,4(3H)-dione of formula (I)

100 mL (2182 mmol) of dimethyl carbonate, 20.0 g (145 mmol) of potassium carbonate and 20.0 g (146 mmol) of salicylamide of formula (II) are added under nitrogen atmosphere and at room temperature in a 250 mL 4-neck flask equipped with a mechanical stirrer. The mixture is then heated to 130°C. After 36 hours at 130°C, the suspension is cooled down to 0°C and the reaction is quenched with a saturated solution of ammonium chloride. In addition, 40 mL of ethyl acetate and 20 mL of methanol are added, the mixture is heated to 60°C and the phases are separated. The solvent of the organic phase is concentrated under vacuum until dryness. The so obtained solid is filtered off on a Buchner filter and washed with ethyl acetate providing 2.5 g of 2H-l,3-benzoxazine-2,4(3H)-dione, or Carsalam, of formula (I) as a white solid with an HPLC purity of 100.0% measured at 245 nm and with a yield of 11%. ¾-NMR (300 MHz, DMSO-de) d: 12.02 (bs, 1H); 7.91 (d, 7=12.9 Hz, 1H), 7.77 (t, 7=6.0 Hz, 1H), 7.41-7.36 (m, 2H).