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WO2019116169A1 - Canagliflozine sensiblement exempte d'impureté hydroperoxyde - Google Patents

Canagliflozine sensiblement exempte d'impureté hydroperoxyde Download PDF

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Publication number
WO2019116169A1
WO2019116169A1 PCT/IB2018/059662 IB2018059662W WO2019116169A1 WO 2019116169 A1 WO2019116169 A1 WO 2019116169A1 IB 2018059662 W IB2018059662 W IB 2018059662W WO 2019116169 A1 WO2019116169 A1 WO 2019116169A1
Authority
WO
WIPO (PCT)
Prior art keywords
canagliflozin
solvent
acetate
process according
solution
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/IB2018/059662
Other languages
English (en)
Inventor
Mahesh Nagarimadugu
Sivakumaran Meenakshisunderam
Velladurai Hero
Rajasekhara Raju KONDURU
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.)
Aurobindo Pharma Ltd
Original Assignee
Aurobindo Pharma 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 Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of WO2019116169A1 publication Critical patent/WO2019116169A1/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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to a process for the preparation of Canagliflozin of formula I, which is substantially free of hydroperoxide impurity.
  • Canagliflozin is chemically known as (lS)-l,5-anhydro-l-[3-[[5-(4- fluorophenyl) -2 -thienyl] -methyl] -4-methylphenyl]-D-glucitol, which is a sodium- glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of the type-2 diabetes mellitus.
  • Canagliflozin is marketed in USA and Europe under the trade name of INVOKANA® in the form of tablets having strengths 100 mg and 300 mg.
  • Type-2 diabetes mellitus is a metabolic disorder involving deregulation of glucose metabolism and insulin resistance, and long-term complications involving the eyes, kidneys, nerves, and blood vessels.
  • Type 2 diabetes mellitus usually develops in adulthood (middle life or later) and is described as the body's inability to make either sufficient insulin (abnormal insulin secretion) or its inability to effectively use insulin (resistance to insulin action in target organs and tissues). More particularly, patients suffering from Type 2 diabetes mellitus have a relative insulin deficiency. That is, in these patients, plasma insulin levels are normal to high in absolute terms, although they are lower than predicted for the level of plasma glucose that is present.
  • US 7,943,582 discloses crystalline Canagliflozin hemihydrate.
  • This patent also discloses the preparation of Canagliflozin hemihydrate, by crystallizing Canagliflozin from a good solvent and water, optionally containing a poor solvent; wherein the good solvent is selected from ketones, esters, alcohols and a mixture of these solvents; poor solvent is selected from alkanes, aromatic hydrocarbons, ethers and a mixture of these solvents.
  • Canagliflozin obtained by the processes described in the prior art often associated with various impurities especially hydroperoxide impurity of formula (II). Unacceptable amounts of impurities are generally formed along with Canagliflozin.
  • Canagliflozin can contain extraneous compounds or impurities that can come from many sources. They can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Impurities in Canagliflozin or any active pharmaceutical ingredient (API) are undesirable and, in extreme cases, might even be harmful to a patient being treated with a dosage form containing the API.
  • API active pharmaceutical ingredient
  • impurities in an API may arise from degradation of the API itself, which is related to the stability of the pure API during storage. Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that any impurities are present in the lowest possible levels, even if structural determination is not possible.
  • the present invention offers a process for the preparation of Canagliflozin, which is substantially free from hydroperoxide impurity.
  • the primary objective of the present invention relates to a process for the preparation of Canagliflozin, which is substantially free from hydroperoxide impurity.
  • the present invention relates to a process for the preparation of Canagliflozin, which is substantially free from hydroperoxide impurity, which comprises:
  • step (b) optionally treating the solution of step (a) with a base;
  • step (a) mass or vice-versa
  • the present invention also relates to a process for the preparation of Canagliflozin, which is substantially free from hydroperoxide impurity, which comprises:
  • step (b) adding an anti-solvent to step (b) mass or vice-versa;
  • the present invention further relates to a process for the preparation of Canagliflozin DL-proline co-crystal, which is substantially free from hydroperoxide impurity, which comprises:
  • step (a) adding Cangaliflozin into a solution or a suspension of step (a);
  • step (b) treating the solution of step (b) with DL-proline in a solvent; and d) crystallizing Canagliflozin DL-proline co-crystals.
  • the present invention relates to a process for the preparation of Canagliflozin, which is substantially free from hydroperoxide impurity, which comprises:
  • step (b) optionally treating the solution of step (a) with a base;
  • step (a) mass or vice-versa
  • organic solvent used in step (a) is selected from the group comprising of methylene chloride, ethylene chloride, ethyl ether, methyl tert-butyl ether, diethyl ether, propyl acetate, methyl acetate, butyl acetate, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, toluene and/or mixtures thereof.
  • co-crystals used in step (a) is selected from amino acid co-crystal such as alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan or methionine, glycine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid or glutamic acid.
  • the amino acid used may be either optically active or racemic form.
  • the optically active amino acid may have either L or D configuration.
  • base is selected from the group comprising of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and/or mixtures thereof.
  • solvate may be defined as a compound formed by solvation, for example as a combination of solvent molecules with molecules or ions of a solute.
  • solvent molecules include water, alcohols and other polar organic solvents.
  • the organic solvent used in step (a) is treated with an antioxidant.
  • the antioxidant used for treating the solvent used in step (a) is selected from BHA (butylated hydroxyanisole), BHT (dibutylhydroxy toluene), PG (propyl gallate), TBHQ (tert-butyl hydroquinone), SMBS (sodium metabisulfite) & TPP (triphenyl phosphine).
  • BHA butylated hydroxyanisole
  • BHT dibutylhydroxy toluene
  • PG propyl gallate
  • TBHQ tert-butyl hydroquinone
  • SMBS sodium metabisulfite
  • TPP triphenyl phosphine
  • organic solvent used in step (a) is treated with antioxidant which involves the dissolution of catalytic quantity of antioxidant in an organic solvent to obtain organic solvent which is treated with an antioxidant.
  • the organic solvent is optionally concentrated to remove water and striped of with same or different organic solvent before the addition of anti-solvent.
  • the anti-solvent is selected from the group comprising of hydrocarbons such as hexane, heptane, cyclohexane and the like.
  • the present invention also relates to a process for the preparation of Canagliflozin, which is substantially free from hydroperoxide impurity, which comprises:
  • step (c) adding an anti-solvent to step (c) mass or vice-versa;
  • organic solvent used in step (a) is selected from the group comprising of methylene chloride, ethylene chloride, ethyl ether, methyl tert-butyl ether, diethyl ether, propyl acetate, methyl acetate, butyl acetate, isopropyl acetate, ethyl acetate, methyl isobutyl ketone, toluene and/or mixtures thereof.
  • the antioxidant used for treating the solvent used in step (b) is selected from BHA (butylated hydroxyanisole), BHT (dibutylhydroxytoluene), PG (propyl gallate), TBHQ (tert-butyl hydroquinone), SMBS (sodium metabisulfite) & TPP (triphenyl phosphine).
  • BHA butylated hydroxyanisole
  • BHT dibutylhydroxytoluene
  • PG propyl gallate
  • TBHQ tert-butyl hydroquinone
  • SMBS sodium metabisulfite
  • TPP triphenyl phosphine
  • the organic solvent is optionally concentrated to remove water and striped of with same or different organic solvent before the addition of anti-solvent.
  • anti-solvent is selected from the group comprising of hydrocarbon such as hexane, heptane, cyclohexane and the like.
  • the present invention further relates to a process for the preparation of Canagliflozin DL-proline co-crystal, which is substantially free from hydroperoxide impurity, which comprises:
  • step (a) adding Cangaliflozin into a solution or a suspension of step (a);
  • step (a) & step (c) treating the solution of step (b) with DL-proline in a solvent; and d) crystallizing Canagliflozin DL-proline co-crystals.
  • the solvent used in step (a) & step (c) is selected from water or mixture of water and water miscible organic solvent; wherein water miscible organic solvent is selected from methanol, ethanol, 1 -propanol, isopropanol and/or mixtures thereof.
  • the antioxidant used for treating the solvent used in step (a) is selected from BHA (butylated hydroxyanisole), BHT (dibutylhydroxy toluene), PG (propyl gallate), TBHQ (tert-butyl hydroquinone), SMBS (sodium metabisulfite) & TPP (triphenyl phosphine).
  • BHA butylated hydroxyanisole
  • BHT dibutylhydroxy toluene
  • PG propyl gallate
  • TBHQ tert-butyl hydroquinone
  • SMBS sodium metabisulfite
  • TPP triphenyl phosphine
  • Canagliflozin which is used as a starting material in the present invention can be in any physical form such as crystalline, amorphous, mixture of crystalline and amorphous, solvates, hydrates etc.
  • Canagliflozin that may be used as the input for the processes of the present invention may be obtained by any process including the processes described in the art and optionally can be purified using any method known in the art to enhance its chemical purity.
  • Canagliflozin prepared in accordance with the present invention contains less than about 0.5%, more preferably less than about 0.1%, and even more preferably, less than about 0.05% of the corresponding peroxide impurity as characterized by HPLC and NMR.
  • Canagliflozin obtained by the processes disclosed herein preferably contains hydroperoxide impurity in an amount of less than about 0.25%, more preferably less than 0.15%, still more preferably less than 0.05% and most preferably less than 0.02%.
  • the total purity of the Canagliflozin obtained by the processes disclosed herein is of greater than about 99.9%, specifically greater than about 99.95%, and more specifically greater than about 99.99% as measured by HPLC.
  • EXAMPLE - 1 PROCESS FOR PREPARING CANAGLIFLOZIN SUBSTANTIALLY FREE OF HYDROPEROXIDE IMPURITY
  • EXAMPLE - 2 PROCESS FOR PREPARING CANAGLIFLOZIN DL- PROLINE CO-CRYSTAL SUBSTANTIALLY FREE OF HYDROPEROXIDE IMPURITY
  • Canagliflozin (0.75g) was contaminated with Canagliflozin DL-proline (4.25gm) in a mixture of methanol (lOml) and water (5ml) at 30-35 °C to get clear solution (Hydroperoxide impurity in this solution is 481 ppm).
  • methanol methanol
  • water 5ml
  • Sodium metabisulfite 0.05g was added at 30-35 °C and stirred for lh at 30-35 °C. Dilute the obtained reaction mass with water (45ml) and stirred for 10 mins sodium carbonate solution (lOml, 10% w/w) was added at 25-30 °C and stirred the solution for 30mins.
  • Organic layer contains product was separated and washed with mixture of DM water (22.5 ml) and methanol (2.5 ml) at 20-30 °C.
  • the separated organic layer was distilled under vacuum at 20-30°C.
  • the residue was dissolved in methyl-tert-butyl ether solution at 40-45°C.
  • the solution was treated with carbon at 45-50 °C, filtered, washed with methyl-tert-butyl ether and cooled to 20-30 °C.
  • the obtained solution was dropped to cyclohexane (100 ml) at 20-25 °C and stirred. Solid was filtered under nitrogen atmosphere and dried at 55-60°C.
  • the organic layer was distilled under vacuum at 35-45 °C until the water content of the concentrated mass is less than or equal to 0.5% w/w and no more methylene chloride distils out.
  • the residue was dissolved in methyl-tert-butyl ether (400 ml) at 40-45°C.
  • the solution was treated with carbon at 45-50 °C, filtered, washed with methyl-tert- butyl ether and cooled to 20-30 °C.
  • the obtained solution was dropped to cyclohexane (2000 ml) at 20-25 °C and stirred. Solid was filtered under nitrogen atmosphere and dried at 55-60°C.

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

Abstract

La présente invention concerne un procédé de préparation de canagliflozine (I), qui est sensiblement exempte d'impureté hydroperoxyde (II).
PCT/IB2018/059662 2017-12-15 2018-12-05 Canagliflozine sensiblement exempte d'impureté hydroperoxyde Ceased WO2019116169A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201741045226 2017-12-15
IN201741045226 2017-12-15

Publications (1)

Publication Number Publication Date
WO2019116169A1 true WO2019116169A1 (fr) 2019-06-20

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/059662 Ceased WO2019116169A1 (fr) 2017-12-15 2018-12-05 Canagliflozine sensiblement exempte d'impureté hydroperoxyde

Country Status (1)

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WO (1) WO2019116169A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116410163A (zh) * 2023-04-13 2023-07-11 南京正大天晴制药有限公司 一种达格列净过氧化物的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016016852A1 (fr) * 2014-07-31 2016-02-04 Sun Pharmaceutical Industries Limited Procédé de purification de canagliflozine
WO2017093949A1 (fr) * 2015-12-04 2017-06-08 Dr. Reddy's Laboratories Limited Canagliflozine sensiblement pure

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016016852A1 (fr) * 2014-07-31 2016-02-04 Sun Pharmaceutical Industries Limited Procédé de purification de canagliflozine
WO2017093949A1 (fr) * 2015-12-04 2017-06-08 Dr. Reddy's Laboratories Limited Canagliflozine sensiblement pure

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116410163A (zh) * 2023-04-13 2023-07-11 南京正大天晴制药有限公司 一种达格列净过氧化物的制备方法

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