WO2021165339A1 - Préparation d'un analgésique non stéroïdien - Google Patents

Préparation d'un analgésique non stéroïdien Download PDF

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Publication number
WO2021165339A1
WO2021165339A1 PCT/EP2021/053917 EP2021053917W WO2021165339A1 WO 2021165339 A1 WO2021165339 A1 WO 2021165339A1 EP 2021053917 W EP2021053917 W EP 2021053917W WO 2021165339 A1 WO2021165339 A1 WO 2021165339A1
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WO
WIPO (PCT)
Prior art keywords
formula
sodium
potassium
carbonate
process according
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PCT/EP2021/053917
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English (en)
Inventor
Gabriele Razzetti
Matteo MORELLI
Niccolò SANTILLO
Graziano Fusini
Alessandro Restelli
Andrea Malvestiti
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Dipharma Francis S.R.L.
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Application filed by Dipharma Francis S.R.L. filed Critical Dipharma Francis S.R.L.
Publication of WO2021165339A1 publication Critical patent/WO2021165339A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
    • C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D265/24—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in positions 2 and 4
    • C07D265/26—Two oxygen atoms, e.g. isatoic anhydride
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms

Definitions

  • the invention relates to a new process for preparing 2H-l,3-benzoxazine-2,4(3H)- dione, also known as Carsalam.
  • 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.
  • an inorganic base for example potassium carbonate or sodium hydroxide.
  • 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.
  • 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.
  • 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.
  • 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.
  • Object of the invention is a process for obtaining 2H-l,3-benzoxazine-2,4(3H)- dione of formula (I), comprising:
  • R and R' which can be the same or different, are a C1-C6 alkyl group; in presence of a base.
  • 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.
  • 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.
  • alkali or alkaline earth metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide or barium hydroxide
  • an alkaline or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate
  • a C1-C6 alcoholate such as sodium methoxide, potassium methoxide, sodium ethoxide
  • 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.
  • 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.
  • 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.
  • 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.
  • an aprotic polar solvent such as dimethyl
  • 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.
  • 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.
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • the acid is hydrochloric acid or acetic acid.
  • the product is isolated by filtration, optionally rinsed with a solvent, and then dried under vacuum.
  • 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%.
  • 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%,
  • 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).
  • 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)
  • 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.
  • 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.
  • a 8-halo-octanoic acid such as 8-bromo-octanoic acid or 8-chloro-octanoic acid
  • the 8-halo-octanoic acid e.g. 8-bromo- octanoic acid or 8-chloro-octanoic acid
  • protecting groups of the carboxylic 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.
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

L'invention concerne un nouveau procédé de préparation de 2H-1,3-benzoxazine-2,4(3H)-dione.
PCT/EP2021/053917 2020-02-18 2021-02-17 Préparation d'un analgésique non stéroïdien WO2021165339A1 (fr)

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Application Number Priority Date Filing Date Title
IT102020000003251A IT202000003251A1 (it) 2020-02-18 2020-02-18 Preparazione di un analgesico non steroideo
IT102020000003251 2020-02-18

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117466765A (zh) * 2023-12-27 2024-01-30 成都道合尔医药技术有限公司 8-(2-羟基苯甲酰胺基)辛酸钠及其合成方法

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB950065A (en) 1960-01-25 1964-02-19 Aspro Nicholas Ltd Pharmaceutical preparations comprising 1:3-benzoxazine-2:4-dione
US3409615A (en) 1964-10-01 1968-11-05 Aspro Nicholas Ltd Process for the preparation of 1:3-benzoxazine-2:4-diones
EP0366177A1 (fr) 1988-10-19 1990-05-02 ENICHEM SYNTHESIS S.p.A. Procédé de préparation de carbonates de dialkyle
EP0460735A2 (fr) 1990-06-04 1991-12-11 ENICHEM SYNTHESIS S.p.A. Procédé et production du carbonate de diméthyle
EP0742198A1 (fr) 1995-05-12 1996-11-13 Ube Industries Limited Procédé de production continue du carbonate de diméthyle
US5591883A (en) 1994-09-29 1997-01-07 Chang Chun Plastics Co. Ltd. Process for preparing carbonate compounds
US5902894A (en) 1998-08-26 1999-05-11 Catalytic Distillation Technologies Process for making dialkyl carbonates
WO2000046182A1 (fr) * 1999-02-05 2000-08-10 Emisphere Technologies, Inc. Procede de preparation de salicylamides alkyles
WO2001070219A1 (fr) 2000-03-21 2001-09-27 Emisphere Technologies, Inc. Procede de preparation de salicylamides alkyles par un agent intermediaire dicarboxylate
US6392078B1 (en) 2000-06-12 2002-05-21 Catalytic Distillation Technologies Process and catalyst for making dialkyl carbonates
WO2008028859A1 (fr) 2006-09-07 2008-03-13 F. Hoffmann-La Roche Ag Procédé de fabrication de snac (salcaprozate sodium)
CN104974060A (zh) 2015-04-24 2015-10-14 上海楷树化学科技有限公司 一种8-(2-羟基苯甲酰胺基)辛酸钠的制备方法

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB950065A (en) 1960-01-25 1964-02-19 Aspro Nicholas Ltd Pharmaceutical preparations comprising 1:3-benzoxazine-2:4-dione
US3409615A (en) 1964-10-01 1968-11-05 Aspro Nicholas Ltd Process for the preparation of 1:3-benzoxazine-2:4-diones
EP0366177A1 (fr) 1988-10-19 1990-05-02 ENICHEM SYNTHESIS S.p.A. Procédé de préparation de carbonates de dialkyle
EP0460735A2 (fr) 1990-06-04 1991-12-11 ENICHEM SYNTHESIS S.p.A. Procédé et production du carbonate de diméthyle
US5591883A (en) 1994-09-29 1997-01-07 Chang Chun Plastics Co. Ltd. Process for preparing carbonate compounds
EP0742198A1 (fr) 1995-05-12 1996-11-13 Ube Industries Limited Procédé de production continue du carbonate de diméthyle
US5902894A (en) 1998-08-26 1999-05-11 Catalytic Distillation Technologies Process for making dialkyl carbonates
WO2000046182A1 (fr) * 1999-02-05 2000-08-10 Emisphere Technologies, Inc. Procede de preparation de salicylamides alkyles
WO2001070219A1 (fr) 2000-03-21 2001-09-27 Emisphere Technologies, Inc. Procede de preparation de salicylamides alkyles par un agent intermediaire dicarboxylate
US6392078B1 (en) 2000-06-12 2002-05-21 Catalytic Distillation Technologies Process and catalyst for making dialkyl carbonates
WO2008028859A1 (fr) 2006-09-07 2008-03-13 F. Hoffmann-La Roche Ag Procédé de fabrication de snac (salcaprozate sodium)
CN104974060A (zh) 2015-04-24 2015-10-14 上海楷树化学科技有限公司 一种8-(2-羟基苯甲酰胺基)辛酸钠的制备方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
GREENE, T.W.WUTS, P.G.M.: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS INC.
SHAPIRO ET AL., J. AM. CHEM. SOC., vol. 79, 1957, pages 2811 - 2814

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117466765A (zh) * 2023-12-27 2024-01-30 成都道合尔医药技术有限公司 8-(2-羟基苯甲酰胺基)辛酸钠及其合成方法
CN117466765B (zh) * 2023-12-27 2024-03-15 成都道合尔医药技术有限公司 8-(2-羟基苯甲酰胺基)辛酸钠及其合成方法

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