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WO2017093949A1 - Canagliflozine sensiblement pure - Google Patents

Canagliflozine sensiblement pure Download PDF

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Publication number
WO2017093949A1
WO2017093949A1 PCT/IB2016/057286 IB2016057286W WO2017093949A1 WO 2017093949 A1 WO2017093949 A1 WO 2017093949A1 IB 2016057286 W IB2016057286 W IB 2016057286W WO 2017093949 A1 WO2017093949 A1 WO 2017093949A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
canagliflozin
formula
less
substantially free
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/IB2016/057286
Other languages
English (en)
Inventor
Dasyam SEETHA
Shah RAVI
Andiappan Murugan
Kondlapudi PADMAJA REDDY
G Saravanan
Kaipu RAMA KRISHNA REDDY
Sonawane SWAPNIL
Vilas Hareshwar Dahanukar
Rodda SWAPNA
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.)
Dr Reddys Laboratories Ltd
Original Assignee
Dr Reddys 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 Dr Reddys Laboratories Ltd filed Critical Dr Reddys Laboratories Ltd
Publication of WO2017093949A1 publication Critical patent/WO2017093949A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present application relates to a process for the preparation of substantially pure canagliflozin.
  • Canagliflozin is chemically described as 1 -([p-D-glucopyranosyl)-4-methyl-3-[5-(4- fluoro phenyl)-2-thienylmethyl]benzene. It has the chemical structure:
  • the US patent 7943788 discloses Canagliflozin in example 84, which is prepared in accordance with examples 1 through 4.
  • the examples disclose the isolation of the crude desired compound in the form of a residue, which is then purified by column chromatography.
  • the US patent 7943582 discloses crystalline form of Canagliflozin hemihydrate and process for its preparation.
  • Innovator's tablet of Canagliflozin (Invokana) by liquid chromatography method illustrated below, it is found that Innovator's Canagliflozin has an impurity eluting at an RT of about 1 1 minutes and an RRT of about 0.53. After LC- MS and NMR analysis the impurity eluting at an RT of about 1 1 minutes and an RRT of about 0.53, it is determined to be having the structure of formula I:
  • Sample preparation Taken 15mg of canagliflozin sample in to 10ml volumetric flask dissolved and diluted up to the mark with diluent.
  • the present application provides canagliflozin substantially free of compound of formula I.
  • the present application provides amorphous form of canagliflozin substantially free of compound of formula I.
  • the present application provides crystalline form of canagliflozin substantially free of compound of formula I.
  • the present application provides storage stable amorphous form of canagliflozin substantially free of compound of formula I.
  • the present application provides amorphous form of canagliflozin having a particle size D[0.9] of less than about 100 or less than about 80 or less than about 50 or less than about 40 or less than about 30 or less than about 20 or less than about 10 microns which is substantially free of compound of formula I.
  • the present application provides a process for the preparation of canagliflozin substantially free of compound of formula I, comprising: a) conversion of a compound 5 to Compound 18a' using compound 13:
  • Ri is an alkyl group.
  • the present application provides a process for the preparation of canagliflozin substantially free of compound of formula I, comprising: a) conversion of a compound 5 to Compound 1 8a' using compound 13:
  • the present application provides a process for the preparation of amorphous canagliflozin substantially free of compound of formula I, comprising: a) conversion of a compound 5 to Compound 1 8a' using compound 13:
  • the present application provides a process for the preparation of substantially pure Canagliflozin substantially free of compound of formula I, comprising isolating canagliflozin in the presence of an anti-oxidant.
  • the present application provides a substantially pure compound 18a', which is substantially free of impurity of formula A.
  • the present application provides a process for the preparation of a substantially pure compound 18a', which is substantially free of impurity of formula A, comprising: purification of compound 18a' by precipitation from a solvent.
  • the present application provides substantially pure canagliflozin, which is substantially free of impurity of formula A.
  • the present application provides a process for the preparation of a substantially pure canagliflozin, which is substantially free of impurity of formula A, comprising:
  • the present application provides a process for the preparation of Canagliflozin, comprising reducing a compound of formula 6 in the presence of AICI 3 .
  • R1 is as defined above.
  • the present application provides an isolated compound of formula A:
  • substantially pure refers to the purity of the material which is at least about 98.0 %, at least about 98.5 %, at least about 99.0 %, at least about 99.1 %, at least about 99.2 %, at least about 99.3 %, at least about 99.4 %, at least about 99.5 %, at least about 99.6 %, at least about 99.7 %, at least about 99.8 %, at least about 99.9 % or 100 % as measured by a liquid chromatography method.
  • substantially free of refers to the level of impurity present in the material which is less than about 0.020 % or less than about 0.010 % or less than about 0.009 % or less than about 0.008 % or less than about 0.007% or less than about 0.006 % or less than about 0.005 % or less than about 0.004 % or less than about 0.003 % or less than about 0.002 % or less than about 0.001 %.
  • Room temperature refers to 'the temperatures of the thing close to or same as that of the space, e.g., the room or fume hood, in which the thing is located'.
  • room temperature can be from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
  • the reaction time should be sufficient to complete the reaction which depends on scale and mixing procedures, as is commonly known to one skilled in the art.
  • the reaction time can vary from about few minutes to several hours.
  • the reaction time can be from about 10 minutes to about 24 hours, or any other suitable time period.
  • reagent may be added at a rate of for example at least about 1 ml/minute or about 1 .5 ml/minute or about 2 ml/minute or about 2.5 ml/minute or about 3ml/minute or any other suitable rate.
  • reactions of the processes described herein can be carried out in air or under an inert atmosphere.
  • reactions containing reagents or products that are substantially reactive with air can be carried out using air-sensitive synthetic techniques that are well known to the person skilled in art.
  • the isolation may be effected by methods such as, removal of solvent, crash cooling, flash evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, freeze drying, or any other suitable fast evaporation technique.
  • the isolated crystalline form of Canagliflozin may contain some amount of occluded mother liquor or higher than desired level of impurities. If desired, the crystalline form may be washed with a solvent or a mixture of solvents to wash out the impurities.
  • Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, less than about 0°C, less than about -10°C, less than about -40°C or any other suitable temperatures.
  • the crystalline product can be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller, hammer mills and jet mills.
  • Suitable column for carrying out said chromatography method may be selected from the group comprising Betasil C8, ACE C18-AR, Bonus RP 18, Inertsil C18, sunfire C18 or any other suitable column.
  • the column can be ACE C18-AR.
  • the length of the column may vary from about 150 mm to about 250 mm. preferably the column length is about 250 mm.
  • the diameter of the column may vary from about 4 mm to about 4.6 mm. preferably the column diameter is about 4.6 mm.
  • the particle size of the packing material within the column may vary from about 3 ⁇ to about 5 ⁇ . Preferable particle size of the packing material can be 5 Dm.
  • the present application provides substantially pure compound 18a', which is substantially free of impurity of formula A.
  • the present application provides a process for the preparation of a substantially pure compound 18a', which is substantially free of impurity of formula A, comprising: purification of compound 18a' by precipitation from a solvent.
  • the solvent used in the preparation of substantially pure compound 18a' can be an organic solvent or water or mixtures thereof.
  • the organic solvent can be selected from but not limited to isopropylacetate, dihloromethane, methyltertiarybutyl ether or mixtures thereof.
  • the present application provides substantially pure canagliflozin, which is substantially free of impurity of formula A.
  • the present application provides a process for the preparation of a substantially pure canagliflozin, which is substantially free of impurity of formula A, comprising:
  • the substantially pure compound 18a' is converted to canagliflozin by any of the methods known in the art.
  • the compound 6 can be converted to canagliflozin by reducing compound 6 with TES (triethyl silane) in presence of AICI 3 .
  • the reaction can be carried out in any suitable solvent such as dichloromethane.
  • the said reaction can be carried out at a temperature of about -20 to about 20°C. More preferably, at a temperature of about -15 to about 15°C; most preferably at a temperature of about -5 to about 5°C.
  • the obtained Canagliflozin can be isolated from a solution of Canagliflozin in a solvent comprising isopropyl acetate, isopropyl alcohol or mixtures thereof optionally to provide crystalline form of Canagliflozin.
  • the present application provides a process for the preparation of substantially pure Canagliflozin substantially free of compound of formula I, comprising isolating canagliflozin in the presence of an anti-oxidant.
  • the substantially pure canagliflozin substantially free of compound of formula I as used herein can be crystalline or amorphous.
  • the anti-oxidant that can be used in the said isolation can be selected from but not limited to, butylated hydroxyanisole (BHA), butylated hydroxytolune (BHT), sodium metabisulfite (SMB), propyl gallate (PG), cysteine (CYS) or any other suitable antioxidant.
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytolune
  • SMB sodium metabisulfite
  • PG propyl gallate
  • cysteine CYS
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytolune
  • BHT butylated hydroxytolune
  • Canagliflozin may be effected by methods such as, filtration by gravity or by suction, centrifugation, decantation, removal of solvent, cooling, slow cooling, crash cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or the like or combinations thereof. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
  • isolated form of Canagliflozin may be washed with a solvent or a mixture of solvents.
  • Suitable temperatures for isolation may be less than about 120°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures.
  • the product can be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller, hammer mills and jet mills.
  • the present application provides an isolated compound of formula A.
  • dichloromethane (25 ml) and aluminiumchloride (14.5 gm) were added and cooled to -5°C and then acetonitrile (61 ml) was added for about 20 minutes.
  • acetonitrile (61 ml) was added for about 20 minutes.
  • triethylsilane (10.8 gm) was added for about 30 minutes at the same temperature.
  • dichloromethane (37 ml) and 2S,3R,4S,5S,6R)-2-(3-((5-(4- fluorophenyl)thiophen-2-yl)methyl)-4-methylphenyl)-6-(hydroxymethyl)-2- methoxytetrahydro-2H-pyran-3,4,5-triol (25 mg) were added and maintained for about 1 hour.
  • Methyltertiarybutylether 150 ml was added and distilled under vacuum for about 40 minutes at 40°C.
  • Methyltertiarybutylether 150 ml was added and distilled under vacuum for about 30 minutes and cooled to room temperature. At this temperature water (2 ml) was added and maintained for about 6 hours and filtered and washed with methyltertiarybutylether (25 ml) to give canagliflozin crude (16 gm) compound.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention concerne de la canagliflozine sensiblement pur et un procédé de préparation de canagliflozine sensiblement pure. La présente invention concerne en outre des composés sensiblement purs 18a' et un procédé de préparation du composé sensiblement pur 18a'.
PCT/IB2016/057286 2015-12-04 2016-12-02 Canagliflozine sensiblement pure Ceased WO2017093949A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN6500CH2015 2015-12-04
IN6500/CHE/2015 2015-12-04
IN201641000430 2016-01-06
IN201641000430 2016-01-06
IN201641004808 2016-02-11
IN201641004808 2016-02-11

Publications (1)

Publication Number Publication Date
WO2017093949A1 true WO2017093949A1 (fr) 2017-06-08

Family

ID=58796414

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/057286 Ceased WO2017093949A1 (fr) 2015-12-04 2016-12-02 Canagliflozine sensiblement pure

Country Status (1)

Country Link
WO (1) WO2017093949A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107540648A (zh) * 2017-08-09 2018-01-05 江苏工程职业技术学院 一种达格列净的制备方法
CN107573311A (zh) * 2017-08-09 2018-01-12 江苏工程职业技术学院 一种达格列净的合成方法
WO2019116169A1 (fr) * 2017-12-15 2019-06-20 Aurobindo Pharma Limited Canagliflozine sensiblement exempte d'impureté hydroperoxyde
CN111077234A (zh) * 2018-10-19 2020-04-28 重庆医药工业研究院有限责任公司 一种用液相色谱法分离测定卡格列净及其杂质的方法
WO2020157644A1 (fr) * 2019-01-31 2020-08-06 Laurus Labs Limited Procédé de préparation de canagliflozine amorphe sensiblement exempte d'impureté hydroperoxyde

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050233988A1 (en) * 2003-08-01 2005-10-20 Tanabe Seiyaku Co., Ltd. Novel compounds
US20090233874A1 (en) * 2007-09-10 2009-09-17 Abdel-Magid Ahmed F Process for the preparation of compounds useful as inhibitors of sglt
CN103601715A (zh) * 2013-11-22 2014-02-26 沈阳化工大学 一种2-(4-氟苯基)噻吩的分离提纯方法
WO2016098016A1 (fr) * 2014-12-17 2016-06-23 Dr. Reddy’S Laboratories Limited Procédé de préparation d'inhibiteurs de sglt2

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050233988A1 (en) * 2003-08-01 2005-10-20 Tanabe Seiyaku Co., Ltd. Novel compounds
US20090233874A1 (en) * 2007-09-10 2009-09-17 Abdel-Magid Ahmed F Process for the preparation of compounds useful as inhibitors of sglt
CN103601715A (zh) * 2013-11-22 2014-02-26 沈阳化工大学 一种2-(4-氟苯基)噻吩的分离提纯方法
WO2016098016A1 (fr) * 2014-12-17 2016-06-23 Dr. Reddy’S Laboratories Limited Procédé de préparation d'inhibiteurs de sglt2

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107540648A (zh) * 2017-08-09 2018-01-05 江苏工程职业技术学院 一种达格列净的制备方法
CN107573311A (zh) * 2017-08-09 2018-01-12 江苏工程职业技术学院 一种达格列净的合成方法
WO2019116169A1 (fr) * 2017-12-15 2019-06-20 Aurobindo Pharma Limited Canagliflozine sensiblement exempte d'impureté hydroperoxyde
CN111077234A (zh) * 2018-10-19 2020-04-28 重庆医药工业研究院有限责任公司 一种用液相色谱法分离测定卡格列净及其杂质的方法
CN111077234B (zh) * 2018-10-19 2023-09-15 重庆医药工业研究院有限责任公司 一种用液相色谱法分离测定卡格列净及其杂质的方法
WO2020157644A1 (fr) * 2019-01-31 2020-08-06 Laurus Labs Limited Procédé de préparation de canagliflozine amorphe sensiblement exempte d'impureté hydroperoxyde

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