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WO2018158777A1 - Procédé amélioré pour la préparation de chlorthalidone - Google Patents

Procédé amélioré pour la préparation de chlorthalidone Download PDF

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Publication number
WO2018158777A1
WO2018158777A1 PCT/IN2018/050103 IN2018050103W WO2018158777A1 WO 2018158777 A1 WO2018158777 A1 WO 2018158777A1 IN 2018050103 W IN2018050103 W IN 2018050103W WO 2018158777 A1 WO2018158777 A1 WO 2018158777A1
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WO
WIPO (PCT)
Prior art keywords
formula
chlorthalidone
compound
water
peroxide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IN2018/050103
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English (en)
Inventor
Maheshkumar Gadakar
Ghanshyam WAGH
Yogesh Wakchaure
Ponpandian Thanasekaran
Dnyandeo PUNDE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mylan Laboratories Ltd
Original Assignee
Mylan Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mylan Laboratories Ltd filed Critical Mylan Laboratories Ltd
Publication of WO2018158777A1 publication Critical patent/WO2018158777A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1

Definitions

  • the present invention relates to an improved process for the preparation of chlorthalidone. BACKGROUND OF THE INVENTION
  • chlorthalidone 3-hydroxy-3-(3'-sulfamyI-4'- chlorophenyl)phthalimidine and is represented by the structural formula 1 shown below.
  • Chlorthalidone is used to treat high blood pressure and fluid retention caused by various conditions, including heart disease. Chlorthalidone also may be used to treat patients with diabetes insipidus and certain electrolyte disturbances and to prevent kidney stones in patients with high levels of calcium in their blood. Chlorthalidone is a valuable pharmaceutical and has been recently prescribed for use in combination with other anti-hypertensive agents.
  • Chlorthalidone, its related compounds and their methods of preparation were first disclosed in Helv. Chim. Acta 42, 1085, (1959) and also in United States Patent No. 3,055,904.
  • United States Patent No. 4,331,600 and International Patent Application Publication No. WO2005065046 also disclose a process for the preparation of chlorthalidone.
  • the present disclosure provides an improved process of making chlorthalidone that is both feasible on a large scale and industrial level and results in a product with high purity.
  • the present invention provides a process for the preparation of compound of formula 10.
  • formula 10 may be prepared by a process that includes the step of treating compound of formula 9 with a chlorinating agent in the presence of chlorosulphonic acid.
  • the chlorinating agent is phosphorus oxychloride.
  • the present invention provides a process of converting the compound of Formula 10 to chlorthalidone comprising the steps of following steps: a. reacting the compound of formula 10 with ammonia to obtain a compound of formula 11
  • the ammonia may be gaseous or aqueous ammonia and this reaction is carried out in a solvent.
  • suitable solvents include, but are not limited to, water, methanol, acetone, dimethyl formamide, dimethylacetamide, and mixtures thereof.
  • the step of converting the compound of formula 11 to crude chlorthalidone is carried out in presence of a base particularly sodium hydroxide and a peroxide selected from sodium peroxide, barium peroxide, or hydrogen peroxide.
  • the present invention provides a method of purifying crude chlorthalidone using a solvent selected from the group consisting of water, water-miscible polar solvents, and mixtures thereof.
  • a solvent selected from the group consisting of water, water-miscible polar solvents, and mixtures thereof.
  • Particularly useful solvents include, but are not limited to, dimethylformamide, tetrahydrofuran, acetone, dioxane, isopropyl alcohol, methanol, and mixtures thereof.
  • the present invention provides an improved process that is industrially viable for the preparation of chlorthalidone, as summarized in scheme 1 below.
  • Chlorthalidone may be synthesized by first converting a compound of formula 2, which is commercially available, into a compound of formula 8. This may be carried out by reacting a compound of formula 2 with hydroxylamine hydrochloride in the presence of a suitable base and a solvent.
  • suitable bases include, but are not limited to, potassium hydroxide, sodium hydroxide, and mixtures thereof.
  • the base is sodium hydroxide.
  • the solvent is an alcohol.
  • methanol is used as the solvent.
  • a compound of formula 8 may be treated with an acid in the presence of zinc dust to obtain compound of formula 9.
  • suitable acids include, but are not limited to, formic acid, propionic acid, acetic acid, and mixtures thereof.
  • the acid is acetic acid.
  • the compound of formula 9 may be treated with a chlorosulphonic acid in the presence of a chlorinating agent to obtain compound of formula 10.
  • a chlorinating agent is phosphorus oxychloride, as shown below:
  • the compound of Formula 10 may be treated with ammonia in a suitable solvent to obtain compound of Formula 11.
  • the ammonia may be in gaseous form or may be aqueous ammonia.
  • suitable solvents include acetone, water, methanol, dimethyl formamide, dimethylacetamide, and mixtures thereof.
  • the compound of formula 11 may then be treated sequentially with a peroxide followed by a base to obtain a crude chlorthalidone.
  • suitable peroxides include, but are not limited to, hydrogen peroxide, barium peroxide, sodium peroxide, and mixtures thereof.
  • suitable bases include sodium hydroxide, potassium hydroxide and potassium carbonate.
  • adding the peroxide before the base in the conversion of formula 11 to chlorthalidone minimizes the formation of process impurities and aids in providing substantially pure chlorthalidone. This is in contrast to prior art processes such as those disclosed in PCT Int. Pat. App. Pub. No. WO2005065046, wherein this step is carried out by first adding sodium hydroxide followed by a peroxide.
  • Substantially pure chlorthalidone may then be obtained by treating crude chlorthalidone with a solvent.
  • suitable solvents include water or water in a mixture with a water- miscible polar solvent.
  • suitable water-miscible polar solvents include but are not limited to, dimethylformamide, tetrahydrofuran, acetone, dioxane, isopropyl alcohol, methanol, and mixtures thereof.
  • Substantially pure chlorthalidone may then be isolated by removing the solvent. This may be carried out by methods well known in the art, for example, by filtering the chlorthalidone/solvent mixture.
  • the collected solid may be further refined, for example, by drying, to result in substantially pure chlorthalidone.
  • substantially pure means a purity of 99.9% or more when measured by HPLC. By using the methods disclosed herein, this high purity is routinely achievable when chlorthalidone is synthesized in batches suitable for industrial manufacturing.
  • Substantially pure chlorthalidone may be formulated into a pharmaceutical dosage form, for example, one for oral administration such as tablets or capsules.
  • Such tablets or capsules may include other pharmaceutically acceptable excipients such as colloidal silicon dioxide, microcrystalline cellulose, starch, sodium starch glycolate, stearic acid, ammonium chloride, colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate, polyethylene glycol, povidone, hydroxypropyl methyl cellulose, mannitol, fumaric acid, sodium hydroxide, crospovidone, talc, and artificial colorings and flavorings.
  • Some tablets or capsules may contain other active pharmaceutical ingredients such as atenolol, azilsartan, betaxolol, clonidine, losartan, and pharmaceutically acceptable salts thereof.
  • Oral dosage forms containing the substantially pure chlorthalidone as prepared by methods disclosed herein may be particularly useful in the treatment or management of hypertension.
  • tablets containing the substantially pure chlorthalidone as prepared by methods disclosed herein may be co-administered with other antihypertensive agents such as such as atenolol, azilsartan, betaxolol, chlonidine, and pharmaceutically acceptable salts thereof.
  • tablets containing chlorthalidone contain 20 mg or 50 mg of chlorthalidone.
  • Zinc dust (66.15 g ,2.0 eq.) was added portion- wise to a stirred solution of 4-(4'- chlorophenyl)-5,6-benz-2,3-oxazin-l-one (130.0 g, 0.5045 moles, 1 eq.) and acetic acid (1300 ml, 10.0 V) at 70 - 75 °C over a 10 - 15 minute interval. The suspension was stirred for 30 - 40 minutes. An additional portion of zinc dust (33.0 g, 1.0 eq.) was added and stirred for 60 - 70 minutes. The hot solution was filtered through Celite and washed with acetic acid (260 ml, 2.0 V).
  • 3 -(4 '-chlorophenyl) phthalimidine (100.0 g, 1 eq.) was added portion-wise to a stirred solution of chlorosulphonic acid (328 ml, 12 eq.) at 0 - 5 °C.
  • the reaction mass was heated to 75 - 80 °C for 3 - 4 hours then cooled to room temperature.
  • Phosphorus oxychloride (76.0 ml, 2.0 eq.) was added into the reaction mass and then heated to 75 - 80 °C for 2 hours.
  • the reaction mass was then cooled to room temperature and quenched into ice cold water (3000.0 ml, 30.0 V) and stirred for 1 hour at 0 - 5 °C to result in a precipitate.
  • Example-4 Preparation of 2-chloro -5-[(lRS)-l-hydroxy-3-oxo-2,3-dihydro-lH- isoindol-l-yl] benzene sulfonamide (crude chlorthalidone, Formula 1)
  • the pH of the filtrate was adjusted to 4.5 - 5.5 using concentrated hydrochloric acid (90.0 ml) and stirred for 1 hour to result in formation of a precipitate.
  • the reaction mixture was filtered and the collected solid was dried for 6 - 8 hours at 60 °C.
  • the dried product was dissolved in methanol (850 ml, 9.5 V) at 60 - 65 °C and slowly added into water (850 ml, 9.5V) at 45 - 50 °C.
  • the reaction mass was cooled to room temperature and then further cooled to 5-10 °C and stirred for 1 hour.
  • Example-5 Purification of 2-chloro -5-[(lRS)-l-hydroxy-3-oxo-2,3-dihydro-lH- isoindol-l-yl] benzenesulfonamide (crude chlorthalidone)
  • Example-6 Purification of 2-chloro-5-[(lRS)-l-hydroxy-3-oxo-2,3-dihydro-lH- isoindol-l-yl] benzenesulfonamide (crude chlorthalidone) 2-chloro-5- [( 1 RS )- 1 -hydroxy-3 -oxo-2,3 -dihydro- 1 H-isoindol- 1 -yl] benzenesulfonamide (crude chlorthalidone) was added to a stirred mixture of acetone (225 ml, 5.0 V) and water (90 ml, 2.0V) at 25 - 30 °C.
  • the reaction mixture was heated to 45 - 55 °C and stirred for 10 - 15 minutes to get a clear solution.
  • the solution was then cooled to 30 - 35 °C, filtered through 0.45 micron paper and washed with an acetone (8 ml):water (4 ml) mixture.
  • the filtrate was added slowly into water (675 ml, 15.0V) at 56 - 64 °C, maintaining temperature.
  • the reaction mixture was stirred for 30 - 40 minutes then gradually cooled to 40 - 50 °C and stirred for an additional 10 - 15 minutes.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de préparation de chlorthalidone. En particulier, les procédés décrits par la présente invention peuvent être réalisés à l'échelle industrielle et fournissent de la chlorthalidone pratiquement pure.
PCT/IN2018/050103 2017-03-01 2018-02-27 Procédé amélioré pour la préparation de chlorthalidone Ceased WO2018158777A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201741007242 2017-03-01
IN201741007242 2017-03-01

Publications (1)

Publication Number Publication Date
WO2018158777A1 true WO2018158777A1 (fr) 2018-09-07

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PCT/IN2018/050103 Ceased WO2018158777A1 (fr) 2017-03-01 2018-02-27 Procédé amélioré pour la préparation de chlorthalidone

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3055904A (en) 1957-11-04 1962-09-25 Geigy Chem Corp New isoindoline derivatives
EP0051215A2 (fr) * 1980-10-31 1982-05-12 Usv Pharmaceutical Corporation Procédés et intermédiaires pour la synthése de 3-aryl-3-hydroxy-phtalimidines
WO2005065046A2 (fr) 2004-01-02 2005-07-21 Ipca Laboratories Limited Procede industriel efficace pour la production de 3-hydroxy-3-(3'-sulfamyl-4'-chlorophenyl)phtalimidine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3055904A (en) 1957-11-04 1962-09-25 Geigy Chem Corp New isoindoline derivatives
EP0051215A2 (fr) * 1980-10-31 1982-05-12 Usv Pharmaceutical Corporation Procédés et intermédiaires pour la synthése de 3-aryl-3-hydroxy-phtalimidines
US4331600A (en) 1980-10-31 1982-05-25 Usv Pharmaceutical Corporation Intermediates for the synthesis of phthalimidines
WO2005065046A2 (fr) 2004-01-02 2005-07-21 Ipca Laboratories Limited Procede industriel efficace pour la production de 3-hydroxy-3-(3'-sulfamyl-4'-chlorophenyl)phtalimidine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HELV. CHIM. ACTA, vol. 42, 1959, pages 1085

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