IT202000003251A1 - PREPARATION OF A NON-STEROID ANALGESIC - Google Patents

Description

Description of the patent for industrial invention entitled:

PREPARATION OF A NON-STEROID ANALGESIC?

FIELD OF INVENTION

The present invention relates to a new method of preparation of 2H-1,3-benzoxazine-2,4 (3H) -dione, also known as Carsalam.

STATE OF THE TECHNIQUE

2H-1,3-Benzoxazine-2,4 (3H) -dione, or Carsalam, of formula (I),

? known as a non-steroidal analgesic (see Merck Index, XII edition, n.1915).

For example, patent application GB950065A filed on January 25, 1960 claims a pharmaceutical composition comprising Carsalam for use as an analgesic or anxiolytic.

Carsalam? also described in US 3,409,615 which has a filing date of 1 October 1965 and claims a process for obtaining Carsalam which comprises the reaction of salicylamide, or 2-hydroxybenzamide, of formula (II)

with an alkyl ester of chloroformic acid in aqueous solution and in the presence of an inorganic base, for example potassium carbonate or sodium hydroxide. This procedure makes it possible to avoid organic solvents, for example acetonitrile which? previously used by Shapiro et al. in J. Am. Chem. Soc. 79, 1957, 2811-284, as a solvent, which according to the ICH guidelines (ICH Harmonized Tripartite Guideline -Impurities: Guideline for Residual Solvents Q3C (R5)) is part of the class 2 solvents, that is? toxic solvents that should be avoided.

In the processes described in US 3,409,615 and in the publication by Shapiro et al. is used as a reactive ethyl chloroformate, the use of which requires high precautions and controls due to its direct danger, since? the mixture ? corrosive and toxic by inhalation.

There is therefore a need? to have an improved process for the preparation of 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I), which overcomes all the disadvantages caused by the use of ethyl chloroformate and which can be easily used on an industrial scale.

The new process for obtaining 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I) should not only not include the use of ethyl chloroformate, but also the use of toxic organic solvents. Furthermore, this new process should provide for the use of efficient, economical and operationally simple reaction conditions in order to obtain 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I) in an advantageous way, in particularly on an industrial scale and in high yield and purity.

SUMMARY OF THE INVENTION

Object of the invention? a process for obtaining 2H-1,3-benzoxazine-2,4 (3H) -dione, also known as Carsalam, of formula (I)

comprising:

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

- with a dialkylcarbonate of formula (III)

in the presence of a base.

This procedure not only allows to avoid the use of ethyl chloroformate, therefore of a toxic and harmful reagent for the environment, but allows to obtain the 2H-1,3-benzoxazine-2,4 (3H) -dione of formula ( I) in safe conditions and with a high degree of purity, so? to meet the regulatory requirements for API (Active Pharmaceutical Ingredient).

DETAILED DESCRIPTION OF THE INVENTION

Object of the invention? a process for obtaining 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I),

comprising:

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

- with a dialkylcarbonate of formula (III)

where R and R ', which can be the same or different, are a C1-C6 alkyl group;

in the presence of a base.

According to the present invention, the term? Comprising? also includes the terms? consistent? and? essentially consisting of ?.

The salicylamide of formula (II), or a salt thereof,? a known compound and? commercially available or can? be prepared with methods known to a person skilled in the art.

A salicylamide salt of formula (II) comprises salts derived from an appropriate base, for example salts of an alkali metal (such as sodium or potassium), of an alkaline earth metal (such as calcium or magnesium), of ammonium or NR <1> 4 <+>, where R <1>? a C1-C4 alkyl group, such as methyl, ethyl, propyl, isopropyl or butyl, isobutyl or tert-butyl.

The dialkylcarbonate of formula (III)? a known compound and? commercially available or can? be prepared with methods known to a person skilled in the art.

The C1-C6 alkyl group, which can? be linear, branched or cyclic, preferably? a C1-C4 alkyl group, such as methyl, ethyl, propyl, isopropyl or butyl, isobutyl or tert-butyl, or? cyclohexyl. The C1-C6 alkyl group can? be optionally replaced by one or more? halogen atoms, for example chlorine or fluorine.

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

The inorganic base? typically a hydroxide of an alkali or alkaline earth metal, for example sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide; or a carbonate of an alkali or alkaline earth metal, for example sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate; or a C1-C6 alcoholate, for example sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide; or a hydride of an alkali metal, typically sodium hydride or potassium hydride.

Preferably, the inorganic base? sodium or potassium methoxide, or sodium or potassium ethoxide.

An organic base? preferably an aliphatic or heteroaromatic tertiary amine, for example triethylamine, tri-n-butylamine, methyl-piperidine, ethyl-piperidine or pyridine.

The reaction of salicylamide of formula (II), or of a salt thereof, with a dialkylcarbonate of formula (III) optionally can? be carried out in the presence of a solvent.

The solvent in which the reaction can? be performed can? being, for example, an aprotic polar solvent, for example dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile or dimethylsulfoxide; an acyclic or cyclic ether, for example methyl tert-butyl ether, tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; an aprotic apolar solvent, typically toluene; a polar protic solvent, typically a linear or branched C1-C8 alcohol, for example 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.

A favorite solvent? n-butanol.

The reaction of salicylamide of formula (II), or of one of its salt, as defined above, with a dialkylcarbonate 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 0 ° C and 150 ° C. Pi? preferably, the reaction can? be carried out at temperatures equal to or below 140? C, for example at 130? C, 120? C, 110? C, 100? C, 90? C, 80? C, 70? C, or at 60? C.

The reaction of salicylamide of formula (II), or of one of its salt, as defined above, with a dialkylcarbonate of formula (III), as defined above, can? be advantageously carried out using from about 1 to about 10 moles of dialkylcarbonate of formula (III) per mole of salicylamide of formula (II), for example from about 1 to about 8 moles or from about 1 to about 8 moles, preferably from about 1 , 5 to about 4 piers, more? preferably about 2.0, 2.5; 3.0; 3.3; 3.5; 4.0; 4.5 or 5.0 moles.

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

The reaction of salicylamide of formula (II), or a salt thereof, as defined above, with a dialkylcarbonate of formula (III), as defined above, can be be advantageously carried out using from about 10 minutes to 96 hours, for example, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 12 hours, 24 hours, 36 hours or 48 hours.

2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I) obtained according to the process described above can be isolated according to known techniques, for example by filtration or centrifugation, optionally followed by drying under vacuum.

Preferably the product? isolated by bringing the reaction mixture to an acidic pH, typically bringing it to a pH of about 1 to 6, for example to a pH of about 4, 5 or 6. The acid used can be removed. be a strong protic acid, typically a halohydric acid, preferably hydrochloric, a sulfuric acid or a sulphonic acid, preferably paratoluenesulfonic acid, or a C1-C4 carboxylic acid, where the C1-C4 alkyl group can be linear or branched, possibly replaced by one or more? halogen atoms, preferably from one to three chlorine or fluorine atoms, typically formic acid, acetic acid or trifluoroacetic acid.

Pi? preferably the acid? hydrochloric acid or acetic acid.

Preferably the product is isolated by filtration, optionally washed with solvent, followed by drying under vacuum. For example, drying can? be performed at a temperature between approximately 0? C and 100? C, for example at about 30? C, 40? C, 45? C, 50? C or 60? C.

2H-1,3-Benzoxazine-2,4 (3H) -dione of formula (I) cos? obtained has a chemical purity in% area, evaluated by HPLC at 245 nm, greater than or equal to 98%, preferably greater than or equal to 99.8%, for example 99.95% or 99.98%.

Furthermore, the inventors of the present invention have found that 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I) obtained with the present process has an impurity content of formula (IV) or of formula ( V)

less than 0.1%, preferably less than 0.05%, for example 0.03%, 0.01%, 0.005%, 0.001% or 0.0005%, and where R? as defined above.

The impurities of formula (IV) or of formula (V)

where R? as defined above, they are intermediate in the reaction of salicylamide of formula (II) with a dialkylcarbonate of formula (III).

The impurities of formula (IV) or of formula (V), as defined above and where R? methyl, are new compounds and represent a further object of the present invention.

2H-1,3-Benzoxazine-2,4 (3H) -dione of formula (I) cos? obtained has a purity such as to satisfy the regulatory requirements required for APIs.

According to a further aspect of the present invention, 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I) pu? be used as a reaction intermediate, for example the product cos? got pu? be converted into N- (8- [2-hydroxybenzoyl] amino) -caprylic acid of formula (VI)

and if desired converted to a pharmaceutically acceptable salt thereof, for example the sodium or potassium salt.

The invention provides as a further object the use of 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I), as defined above, to obtain the N- (8- [2- hydroxybenzoyl] amino) -capryl) of formula (VI), or a pharmaceutically acceptable salt thereof.

The invention provides as a further object a process for the preparation of 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I), as defined above, to obtain the N- (8- [ 2-hydroxybenzoyl] amino) -capryl) of formula (VI), or a pharmaceutically acceptable salt thereof.

For example, 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I) cos? got pu? be converted into N- (8- [2-hydroxybenzoyl] amino) -caprilic acid of formula (VI), as defined above, by reaction with 8-halocaprilic acid, for example 8-bromocaprilic acid or 8-chlorocaprilic acid, and , if desired, converted to a pharmaceutically acceptable salt thereof. Caprylic acid can be optionally protected with protective groups of the functionality? carboxyl according to the methods well known in the 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 functionality? carboxylic pu? be a C1-C6 alkyl ester group, where the C1-C6 alkyl group? as defined above.

In particular, the conversion of 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I) into N- (8- [2-hydroxybenzoyl] amino) -caprilic acid of formula (VI), or in its pharmaceutically acceptable salt, can it? be carried out in accordance with the procedures described in patent applications WO 2001/70219, WO 2008/028859 or CN104974060.

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

The following example further illustrates the invention.

Example 1. Preparation of 2H-1,3-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 mmoles) of salicylamide of formula (II) are added under nitrogen and at room temperature in a 250 mL 4-neck flask equipped with a mechanical stirrer. The mixture is then heated to 80 ° C and 20 mL (238 mmoles) of dimethylcarbonate are added. After 1 hour at 80 ° C the suspension is cooled to 0 ° C and 70 mL of an aqueous solution of 2 M hydrochloric acid (HCl) are added, bringing the reaction mixture to a pH of 5. The suspension is left under stirring at 0? C for an hour, after which? the solid is filtered on Buchner and washed with n-butanol and water. 9.5 g of 2H-1,3-benzoxazine-2,4 (3H) -dione, or Carsalam, of formula (I) are obtained 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-d6)?: 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).

Claims (10)

CLAIMS 1. A process for obtaining 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I), comprising: - the reaction of salicylamide of formula (II), or of a salt thereof, - with a dialkylcarbonate of formula (III) where R and R ', which can be the same or different, are a C1-C6 alkyl group; in the presence of a base. 2. A process according to claim 1, where the C1-C6 alkyl group, which can? be linear, branched or cyclic,? optionally replaced by one or more? halogen atoms. 3. A process according to claim 2, where the C1-C6 alkyl group? a C1-C4 alkyl group, such as methyl, ethyl, propyl, isopropyl or butyl, isobutyl or tert-butyl; or ? cyclohexyl. 4. A process according to claims 1 to 3, where is the basis? an inorganic base, typically a hydroxide of an alkali or alkaline earth metal, for example sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide; or a carbonate of an alkali or alkaline earth metal, for example sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate; or a C1-C6 alcoholate, for example sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide; or a hydride of an alkali metal, typically sodium hydride or potassium hydride. 5. A proceeding according to claim 4, where the basis? sodium or potassium methoxide, or sodium or potassium ethoxide. 6. A process according to claims 1 to 5, carried out in the absence or in the presence of a solvent. 7. A process according to claim 6, carried out in the presence of a solvent, where the solvent? polar aprotic solvent, for example dimethylformamide, dimethylacetamide, N-methylpyrrolidone, acetonitrile or dimethyl sulfoxide; or an acyclic or cyclic ether, for example methyl tert-butylether, tetrahydrofuran or dioxane; a chlorinated solvent, for example, dichloromethane, dichloroethane, chloroform or chlorobenzene; an aprotic apolar solvent, typically toluene; a polar protic solvent, typically a linear or branched C1-C8 alcohol, for example 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. 8. A process according to claims 1 to 7, where the reaction of salicylamide of formula (II), or of a salt thereof, as defined in claim 1, with a dialkyl carbonate of formula (III), as defined in claims 1 to 3, is carried out at a temperature between about 0 ° C and the reflux temperature of the reaction mixture. 9. A process according to claims 1 to 8, where 2H-1,3-benzoxazine-2,4 (3H) -dione of formula (I), as defined in claim 1, is converted into N- (8-) acid [2-hydroxybenzoyl] amino) -capryl of formula (VI) by reaction with 8-halocaprilic acid, for example 8-bromocaprilic acid or 8-chlorocaprilic acid, and if desired converted to a pharmaceutically acceptable salt thereof, for example the sodium or potassium salt. 10. The compound of formula (IV) or of formula (V) where R? methyl.