WO2016098016A1 - Procédé de préparation d'inhibiteurs de sglt2 - Google Patents

Procédé de préparation d'inhibiteurs de sglt2 Download PDF

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Publication number
WO2016098016A1
WO2016098016A1 PCT/IB2015/059676 IB2015059676W WO2016098016A1 WO 2016098016 A1 WO2016098016 A1 WO 2016098016A1 IB 2015059676 W IB2015059676 W IB 2015059676W WO 2016098016 A1 WO2016098016 A1 WO 2016098016A1
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Prior art keywords
compound
canagliflozin
reaction
stirred
added
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PCT/IB2015/059676
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English (en)
Inventor
Srinivas ORUGANTI
Bhaskar KANDAGATLA
Vilas Hareshwar Dahanukar
Praveen Cherukupally
Asif Mohammad
Venu Nalivela
Murali KONAKALLA
Debjit BASU
Venkata Annapurna Sasi Kala CHEEMALAPATI
Rakeshwar Bandichhor
Murugan ANDIAPPAN
Archan Dey
Ramakrishna Reddy KAIPU
Jithin Jose
Srividya Ramakrishnan
Rajashekhar Totad
Sharad Santu PACHORE
Sateesh MADAVARAM
Sravan Kumar BANDARU
Dattatray S METIL
Peter Joseph Mccormack
Vishnu Vardhana Vema Reddy EDA
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Dr. Reddy’S Laboratories Limited
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Publication of WO2016098016A1 publication Critical patent/WO2016098016A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
    • C07H7/04—Carbocyclic radicals

Definitions

  • Present application relates to the process for the preparation of SGLT2 inhibitors.
  • SGLT2 inhibitors lower the plasma glucose concentration by inhibition of glucose re-uptake in the kidney, without weight gain.
  • SGLT2 inhibitors gliflozins
  • gliflozins such as canagliflozin, dapagliflozin, sergliflozin, ipragliflozin, empagliflozin, and luseogliflozin.
  • SGLT2 inhibitors gliflozins
  • n be represented by general structural formula 1 :
  • Canagliflozin is chemically described as (1 S)-1 ,5-anhydro-1 -[3-[[5-(4- fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol. It has the chemical structure of formula (1 a).
  • Sergliflozin is chemically described as 2-(4-Methoxybenzyl)phenyl-p-D- glucopyranoside. It has the chemical structure of formula (1 c).
  • Ipragliflozin is chemically described as (1 S)-1 ,5-Anhydro-1 -[3-(1 -benzothiophen- 2-ylmethyl)-4-fluorophenyl]-D-glucitol. It has the chemical structure of formula (1 d).
  • Luseogliflozin is chemically described as (1 S)-1 ,5-Anhydro-1 -[5-(4- ethoxybenzyl)-2-methoxy-4-methylphenyl]-1 -thio-D-glucitol. It has the chemical structure of formula (1 f).
  • US patent document 7,943,788 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.
  • US patent document 7,943,582 discloses crystalline hemihydrate form of canagliflozin and process for its preparation.
  • US patent application document US8999941 B2 discloses that amorphous form of Canagliflozin is hygroscopic as per Dynamic vapor sorption (DVS) analysis. Amorphous form undergoes physical changes. Further discloses, the preparation of amorphous Canagliflozin by adding a solution of Canagliflozin in toluene to n-heptane.
  • SGLT2 inhibitors gliflozins
  • preparation of Canagliflozin which results in the control of unwanted a-anomer to a greater extent.
  • Another objective of the present application is to provide a process for the preparation of amorphous form of Canagliflozin and a solid dispersion comprising amorphous form of Canagliflozin.
  • Figure 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline compound 18a' obtained according to example 19.
  • PXRD powder X-ray diffraction
  • Figure 2 is an illustration of a powder X-ray diffraction (PXRD) pattern of crystalline compound 18a' obtained according to example 20.
  • PXRD powder X-ray diffraction
  • Figure 3 is an illustration of modulated DSC thermogram of amorphous form of
  • Figure 4 is an illustration of modulated DSC thermogram of amorphous form of
  • Canagliflozin obtained after 1 st micronization according to example 35 canagliflozin obtained after 1 st micronization according to example 35.
  • Figure 5 is an illustration of modulated DSC thermogram of amorphous form of
  • Figure 6 is an illustration modulated DSC thermogram of amorphous form of
  • Figure 7 is an illustration of a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising Canagliflozin and copovidone.
  • PXRD powder X-ray diffraction
  • Figure 8 is an illustration of a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising Canagliflozin and PVP-K30.
  • PXRD powder X-ray diffraction
  • Figure 9 is an illustration of a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising Canagliflozin and HPMC-AS.
  • PXRD powder X-ray diffraction
  • Figure 10 is an illustration of a powder X-ray diffraction (PXRD) pattern of amorphous solid dispersion comprising Canagliflozin and Eudragit.
  • Figure 1 1 is an illustration of differential scanning thermogram (DSC) of crystalline form of Canagliflozin obtained according to example 36.
  • Figure 1 2 is an illustration of XRD of crystalline form of Canagliflozin obtained according to example 36.
  • Figure 13 is an illustration of XRD of amorphous form of Canagliflozin obtained according to example 50.
  • Figure 14 is an illustrative HPLC method for measuring purity of compound 18a'.
  • Figure 15 is an illustrative HPLC method for measuring purity of canagliflozin (compound 1 a).
  • the present application provides novel synthetic processes for obtaining Canagliflozin and its related intermediates.
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 4 to a compound 6 using a compound 5:
  • the present application provides a process for preparing Dapagliflozin (Compound 1 b) comprising the conversion of a compound 4 to a compound 8 using a compound 7: Compound 4
  • the present application provides a process for preparing Canagliflozin (compound 1 a), comprising the conversion of a compound 1 1 to compound 12:
  • X is suitably selected halogen; and Ri is suitably selected from H or lower alkyl group.
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 12 to a compound 14 using a compound 13:
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 14 to a compound 15: Compound 15 wherein Ri is suitably selected from H or lower alkyl group.
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 15 to Canagliflozin (Compound 1 a):
  • Compound 15 Compound 1a wherein Ri is suitably selected from H or lower alkyl group.
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 14 to a compound 16:
  • Compound 1 4 Compound 1 wherein Ri is suitably selected from H or lower alkyl group.
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 16 to a compound 17:
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 17 to Canagliflozin (Compound 1 a):
  • the present application provides a process for preparing SGLT2 inhibitors (Compound 1 ) comprising the conversion of a compound 18 to Compound 19:
  • Z is H or suitably selected oxygen protecting group
  • Y is suitably selected C, N, O or S
  • Ri is suitably selected from H or lower alkyl group
  • the present application provides a process for preparing SGLT2 inhibitors (Compound 1 ) comprising the conversion of a compound 19 to Compound 1 :
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 14 to Compound 19a:
  • the present application provides a one pot process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 5 to Compound 19a using compound 13:
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 19a to Compound 1 a:
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 5 to Compound 18a' using compound 13:
  • the present application provides a process preparing solid form of Compound 18a' comprising:
  • the present application provides a process for preparing crystalline form of Compound 18a' comprising:
  • the present application provides solid form of compound 18a'.
  • the present application provides a crystalline form of compound 18a'.
  • the present application provides solid form of compound 18a' having a purity of at least 98% as measured by HPLC method.
  • the present application provides crystalline form of compound 18a' having a purity of at least 98% as measured by HPLC method.
  • the present application provides a crystalline form of compound 18a' characterized by one or more of:
  • thermogravimetric analysis shows a mass loss of 0.052%.
  • the present application provides a crystalline form of compound 18a' characterized by X-ray diffraction pattern with peaks at about 10.81 , 13.50, 18.96, 20.99, 23.73 and 30.68 ⁇ 0.2 degrees two-theta.
  • the present application provides a process for preparation of Canagliflozin comprising, conversion of solid form of compound 18a' in to Canagliflozin.
  • the present application provides a process for preparation of Canagliflozin comprising conversion of solid form of compound 18a' with a purity of at least 98% as measured by HPLC in to Canagliflozin with high purity.
  • the present application provides a process for preparation of Canagliflozin comprising, conversion of crystalline form of compound 18a' in to Canagliflozin.
  • the present application provides a process for preparation of Canagliflozin comprising, conversion of crystalline form of compound 18a' with a purity of at least 98% as measured by HPLC in to Canagliflozin with high purity.
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 18a' to Compound 1 a.
  • the present application provides a process for preparing pure Canagliflozin comprising conversion of a compound 6 to Canagliflozin by slow addition of BF3.Etherate to compound 6:
  • Compound 6 Canagliflozin wherein Ri is a lower alkyl group.
  • the present application provides an amorphous form of Canagliflozin with a mean particle size D[4,3] of about 30 microns to about 200 microns.
  • the present application provides an amorphous form of Canagliflozin with a d(0.1 ) particle size of about 0.1 to about 30 microns, a d(0.5) particle size of about 30 microns to about 200 microns and/or a d(0.9) particle size of about 50 microns to about 400 microns.
  • the present application provides a process for the preparation of amorphous form of Canagliflozin, comprising: a) providing a solution of Canagliflozin in a solvent;
  • step b) mixing an anti-solvent and the solution obtained in step a) in a micro mixing reactor;
  • the present application provides a process for the preparation of amorphous form of Canagliflozin, comprising: a) heating, mixing and/or kneading Canagliflozin through an extruder to result in a homogenous melt; b) forcing the resultant melt obtained in step a) through one or more orifices, nozzles, or moulds; c) cooling the extrudate of step b) to yield amorphous form of Canagliflozin;
  • the present application provides a process for the preparation of solid dispersion comprising amorphous Canagliflozin and one or pharmaceutically acceptable excipients, comprising:
  • step b) heating, mixing and/or kneading the resultant blend of step a) through an extruder to result in a homogenous melt;
  • step b) forcing the resultant melt obtained in step b) through one or more orifices, nozzles, or moulds;
  • step c) cooling the extrudate of step c) to yield solid dispersion
  • the present application provides a process for the preparation of amorphous form of Canagliflozin, comprising:
  • the present application provides an amorphous form of Canagliflozin showing a glass transition in modulated DSC thermogram with an onset temperature of at least about 45 °C.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising an amorphous form of Canagliflozin showing a glass transition in modulated DSC thermogram with an onset temperature of at least about 45 °C and one or more pharmaceutically acceptable carriers.
  • the present application provides a process for preparing crystalline form of Canagliflozin by isolating from a solution of Canagliflozin in a solvent comprising isopropyl acetate, isopropyl alcohol or mixtures thereof.
  • the present application provides a process for preparing pure 2-(4-fluorophenyl) thiophene comprising:
  • the present application provides a process for preparing pure 2-(4-fluorophenyl) thiophene comprising:
  • the present application provides a process for preparing pure 2-(4-fluorophenyl) thiophene comprising: a) dissolving 2-(4-fluorophenyl) thiophene in a solvent selected from acetone, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, tetrahydrofuran, ethylacetate; and b) isolating pure 2-(4-fluorophenyl) thiophene by mixing an anti-solvent selected from water, n-hexane, diethylether, 1 ,4-dioxane or mixture of water miscible organic solvents.
  • a solvent selected from acetone, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, tetrahydrofuran, ethy
  • present application provides a process for preparing pure 2-(4-fluorophenyl) thiophene comprising: a) dissolving 2-(4-fluorophenyl) thiophene in isopropyl alcohol, and
  • the present application provides a process for preparing canagliflozin from pure 2-(4-fluorophenyl) thiophene comprising:
  • the present application provides a process for preparing canagliflozin from pure 2-(4-fluorophenyl) thiophene comprising:
  • the present application provides a process for preparing canagliflozin from pure 2-(4-fluorophenyl) thiophene comprising:
  • c) dissolving 2-(4-fluorophenyl) thiophene in a solvent selected from acetone, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, tetrahydrofuran, ethylacetate; and d) isolating pure 2-(4-fluorophenyl) thiophene by mixing an anti-solvent selected from water, n-hexane, diethylether, 1 ,4-dioxane or mixture of water miscible organic solvents.
  • a solvent selected from acetone, methanol, ethanol, isopropyl alcohol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, tetrahydrofuran, ethylacetate
  • d) isolating pure 2-(4-fluorophenyl) thiophene by mixing
  • the present application provides a process for preparing canagliflozin from pure 2-(4-fluorophenyl) thiophene comprising:
  • amorphous form refers to any amorphous solid state which is known to a person skilled in the art.
  • amorphous solids lack the three-dimensional long-range order found in crystalline solids, although short-range order may be present over several molecular dimensions. Due to the lack of three- dimensional long-range order, amorphous solids do not constructively diffract X-rays, as do crystalline solids. Therefore, in X-ray powder diffraction experiments, broad, diffuse haloes are observed instead of well-defined peaks [Journal Of Pharmaceutical Sciences, Vol. 93, no. 1 , January 2004, Page-3].
  • a glass is defined as an amorphous solid that exhibits a glass transition.
  • the "glass transition” is a phenomenon in which the solid amorphous phase exhibits an abrupt change in derivative thermodynamic properties (e.g., heat capacity or thermal expansivity) with a change in temperature [Journal Of Pharmaceutical Sciences, Vol. 93, NO. 1 , January 2004, Page-3].
  • solid dispersion means any solid composition having at least two components.
  • a solid dispersion as disclosed herein includes an active ingredient Canagliflozin dispersed among at least one other component, for example a polymer.
  • the reaction product of a given step can be carried forward to the next step without the isolation of the product i.e., one or more reactions in a given process can be carried out in-situ as one pot process optionally in the presence of the same reagent/s used in a previous step wherever appropriate to do so, to make the process of the present application economical and commercially more viable.
  • reaction product of a given step can be isolated and purified by the methods described herein or the methods known to a person skilled in the art before using in a subsequent step of the process.
  • the isolation of products after completion of the reactions can be effected by removing the solvent.
  • Suitable techniques which can be used for the removal of the solvent include evaporation techniques such as evaporation using a Buchi® Rotavapor®, spray drying, thin film drying, nauta drying, tray drying, freeze drying (lyophilization) or any other suitable technique.
  • Isolated product can be optionally further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, Buchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer.
  • the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 150°C, less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, or any other suitable temperatures.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to several hours.
  • the dried 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.
  • 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.
  • 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.
  • 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.
  • Halo or halogen refers to fluorine, chlorine, bromine, or iodine.
  • any of the processes for preparation of the compounds of the present application it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
  • the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • pure or “high purity” when used in the present application with reference to canagliflozin or compound 18a' refers to a purity of at least about 98% or about 98.5% or about 99% or about 99.5% or about 99.8% or about 99.9% or 100%. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, “pure” as used herein also means that the material contains 99% of one enantiomer or diastereomer, as appropriate. "Substantially pure” as used herein means at least about 98% pure and, likewise, "essentially pure” as used herein means at least about 95% pure.
  • Substantially free of one or more of its corresponding impurities refers to the compound that contains less than about 2%, or less than about 1 %, or less than about 0.5%, or less than about 0.3%, or less than about 0.2%, or less than about 0.1 %, or less than about 0.05%, or less than about 0.03%, or less than about 0.01 %, by weight, of individual impurity.
  • compound 4 can be reacted with compound 5 in presence of alkyl lithium to obtain compound 6.
  • Alkyl lithium includes, methyl lithium, n-propyl lithium, isopropyl lithium, cyclopropyllithium, n-butyl lithium, s-butyl lithium, t-butyl lithium, sec-amyl lithium, tert- amyl lithium, n-hexyllithium, 4-heptyllithium, cyclohexyllithium, triethylmethyllithium, 1 - methylcyclo-pentyllithium, phenyl lithium, mesityl lithium (i.e. 2,4,6-trimethylphenyl lithium), trimethylsilylmethyl lithium, triethylsilylmethyl lithium, adamantyllithium and the like.
  • the alkyl lithium is preferably present in an amount in the range of from about 1 .0 to about 3.0 molar equivalents, or any range therein, more preferably in an amount in the range of from about 2.0 to about 2.5 molar equivalents, or any range therein, most preferably about 2.0 molar equivalents.
  • the compound 4 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein.
  • the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like; at a temperature in the range of from about 0° C. to about -78° C, or any range therein; to yield the corresponding compound 6.
  • organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like.
  • reaction of the compound 4 with the compound 5 can be carried out by lithiating the compound 4, followed by reacting the resultant with the compound 5.
  • the alkyl lithium can be added to a mixture of the compound 4 and the compound 5.
  • Compound 6 can be converted to compound 1 a by the methods know in the art. Methods known in US7943788, US 20090233874, US 20100099883, US 201 10087017, US8772512, US 20130052266, WO 2012140120, WO 2012154812, WO 2013068850, and WO 2013064909, are incorporated herein by reference in their entirety.
  • compound 4 can be reacted with compound 7 in presence of alkyl lithium to obtain compound 8.
  • Alkyl lithium can be as described in the first embodiment herein above.
  • the alkyl lithium is preferably present in an amount as described in first embodiment herein above.
  • the compound 4 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein.
  • the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like; at a temperature in the range of from about 0° C. to about -78° C, or any range therein; to yield the corresponding compound 8.
  • reaction of the compound 4 with the compound 7 can be carried out by lithiating the compound 4, followed by reacting the resultant with the compound 7.
  • the alkyl lithium can be added to a mixture of the compound 4 and the compound 7.
  • Compound 7 can be converted to compound 1 b by the methods known in the art. Methods known in US6414126, US7919598, US7375213, and US7932379 are incorporated herein by reference in their entirety.
  • the conversion of the compound 1 1 to the compound 12 can be carried out using alcohol optionally in presence of acid catalyst.
  • the said conversion can be carried out in presence of solvent.
  • a suitable acid catalyst includes, but not limited to, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, nitric acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, boron trifluoride ammonium chloride, and sulfonic acid ion exchange resins.
  • Alcohol corresponding to lower alkyl group can be used for the conversion.
  • the solvent used include, but not limited to, alcohol solvent, aromatic hydrocarbon solvent, hydrocarbon solvents, ether solvents, polar aprotic solvents, nitrile solvents, or any mixture thereof.
  • dehydrating agent or other means of water removal can be performed during reaction that will drive the equilibrium to the right.
  • Dehydrating agent includes, but not limited to ortho ester such as triethyl orthoformate, trimethyl orthoformate and the like.
  • compound 12 can be reacted with compound 13 in presence of alkyl lithium to obtain compound 14.
  • Alkyl lithium can be as described in the first embodiment herein above.
  • the alkyl lithium is preferably present in an amount as described in the first embodiment herein above.
  • the compound 13 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein.
  • the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like; at a temperature in the range of from about 0° C. to about -78° C, or any range therein; to yield the corresponding compound 14.
  • organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like.
  • reaction of the compound 12 with the compound 13 can be carried out by lithiating the compound 13, followed by reacting the resultant with the compound 12.
  • the alkyl lithium can be added to a mixture of the compound 12 and the compound 13.
  • reaction of the compound 12 with the compound 13 can be carried out, wherein compound 12 is converted to compound 12a before reacting with compound 13.
  • Compound 12 can be converted to compound 12a by reacting with a complex of di(Ci- 4 alkyl) magnesium with lithium chloride such as di(sec-butyl)magnesium with lithium chloride, and the like; or a complex Ci- 4 alkyl magnesium chloride with lithium chloride or a complex of Ci- 4 alkyl magnesium bromide with lithium chloride; wherein the Ci- 4 alkyl is preferably isopropyl or sec-butyl; wherein complex is present in an amount in the range of from about 1 .0 to 1 .5 molar equivalents (relative to the moles of the compound 12); in an organic solvent or mixture thereof, such as toluene, THF, hexane, pentane, MTBE, 1 ,4-dioxane, and the like; at a temperature in the range of from about ambient temperature to about -78° C, or any range therein; to yield the corresponding compound 12a.
  • the compound 12a is reacted with the compound 13; wherein the compound 13 can be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein; in an organic solvent or mixture thereof, such as toluene, THF, hexane, pentane, MTBE, 1 ,4-dioxane, and the like; at a temperature in the range of from about ambient temperature to about -78° C, or any range therein; to yield the corresponding compound 14.
  • the compound of formula 12a can be added to a mixture of the compound 13 in an organic solvent, to yield the compound 14.
  • conversion of the compound 14 to the compound 15 can be carried out using reducing agent.
  • the reducing agent used includes, but not limited to, borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, lithium cyanoborohydride, sodium triacetoxyborohydride, potassium triacetoxyborohydride, also in the presence of suitable additives such as sulfuric acid, methanesulfonic acid, acetic acid, titanium chloride, zinc chloride, cobalt (II) chloride, aluminium chloride, tin chloride, nickel chloride, phosphorus oxychloride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, pyridine, iodine, trifluoroethanol or 1 ,2-ethanedithiol.
  • suitable additives such as sulfuric acid, methanesulfonic acid, acetic acid, titanium chloride, zinc chloride,
  • the molar ratio of the reducing agent that can be used with respect to the compound 14 can be easily derived by a person skilled in the art.
  • the said mole ratio can be about 0.01 , about 0.02, about 0.05, about 0.1 , about 0.2, about 0.5, about 1 .0, about 1 .5, about 2 or any other suitable mole per mole of the compound 14.
  • the conversion can take place in the presence of solvent or in the absence of a solvent.
  • the suitable solvent includes, but not limited to, alcohol solvents, ketone solvents, aromatic hydrocarbon solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, ester solvents, ether solvents, polar aprotic solvents, nitrile solvents, or any mixtures thereof.
  • compound 15 can be converted to compound 1 a (Canagliflozin).
  • the compound 15 can be reacted with a suitably selected acid, such as, Lewis acid, which includes, but not limited to, BF 3 .OEt 2 , BF 3 .THF, aluminum chloride, zinc chloride, iron chloride, and the like; or strong organic acid, which includes, but not limited to, trifluoroacetic acid, methanesulfonic acid and the like; wherein the acid is preferably present in an amount in the range of from about 0.5 to about 10.0 molar equivalents, or any range therein; in the presence of a suitably selected silane reagent such as triisopropylsilane, triethylsilane, tetramethyldisiloxane, and the like, preferably triethylsilane or tetramethyldisiloxane; wherein the silane reagent can be preferably present in an amount in the range of from about 1 .0 to about 10.0 molar equivalents, or any range therein; in an organic solvent or mixture
  • compound 14 can be converted to the compound 16.
  • the reaction conditions such as acid, silane reagent and solvent can be such as described in sixth embodiment.
  • conversion of the compound 16 to the compound 17 can be carried out using reducing agent as described in fifth embodiment.
  • conversion of compound 17 can be converted to compound 1 a (Canagliflozin).
  • the reaction conditions such as acid, silane reagent and solvent can be such as described in sixth embodiment.
  • conversion of a compound 18 to a compound 19 can be carried out in presence of an acid.
  • the suitable acid includes, (+)-Camphor-10- sulfonic acid, (-)-Camphor-I O-suolfonic acid, ( ⁇ )-Camphor-10-sulfonic acid, tnfluoromethanesulfonic acid, borontrifluoride and its various complexes, trifluoroacetic acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, acetic acid, hydrochloric acid, sulphuric acid, methane sulfonic acid, and thionylchoride.
  • the amount of acid for intra molecular glycosidation can be easily derived by a person skilled in the art.
  • the said amount can vary from 0.5 mol% to 40 mol%.
  • the reaction can be accomplished with amount from about 5.0 mol% to about 10.0 mol% of the reagent, relative to one molar equivalent of sugar derivative.
  • the suitable solvent that can be used includes ethers such as tetrahydrofuran, dioxane, diisopropylether, diethylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; esters such as ethyl acetate, isopropyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or dichlorobenzene; aliphatic hydrocarbon solvents such as acetonitrile, methylcyclohexane, cyclohexane, heptane or hexane; aromatic hydrocarbon solvents such as toluene, benzene, chlorobenzene, 4-chlorotoluene, trifluorotoluene, o-xylene, m-xylene or p-xy
  • the conversion of a compound 18 to a compound 19 can take place at a temperature of about -50°C to about 150°C, about 0°C to about 100°C, about 0°C to about 50°C, about room temperature, about reflux temperature of the solvent used in the reaction, or any other suitable temperature, which facilitates the desired reaction to happen without substantially negatively affecting the quality of the substrates or the reaction product.
  • compound 19 can be converted to the compound 1 by reacting with a suitably selected Lewis acid, which includes, but not limited to, BF 3 .OEt 2 , BF 3 .THF, aluminum chloride, zinc chloride, iron chloride, and the like, also in the presence of a suitably selected silane reagent such as described in sixth embodiment; suitable borohydrides and suitable additives such as described in eighth embodiment.
  • a suitably selected Lewis acid which includes, but not limited to, BF 3 .OEt 2 , BF 3 .THF, aluminum chloride, zinc chloride, iron chloride, and the like, also in the presence of a suitably selected silane reagent such as described in sixth embodiment; suitable borohydrides and suitable additives such as described in eighth embodiment.
  • the molar ratio of Lewis acid or borohydride that can be used with respect to the compound 19 can be easily derived by a person skilled in the art.
  • the said mole ratio can be about 0.01 , about 0.02, about 0.05, about 0.1 , about 0.2, about 0.5, about 1 .0, about 1 .5, about 2, about 3 or any other suitable mole per mole of the compound 19.
  • the conversion can take place in the presence of solvent or in the absence of a solvent.
  • the suitable solvent can be such as described in tenth embodiment.
  • conversion of a compound 14 to a compound 19a can be carried out in presence of an acid.
  • the reaction conditions for the said conversion can be such as described in tenth embodiment.
  • the present application provides a one pot process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 5 to Compound 19a using compound 13, wherein intermediate compound 18b is formed by reacting compound 5 and compound 13, further compound 18b is converted to compound 19a without isolation or purification.
  • Compound 5 can be reacted with compound 13 under conditions such as described in first embodiment to obtain compound 18b.
  • reaction of the compound 5 with the compound 13 can be carried out, wherein compound 5 is converted to compound 5a before reacting with compound 13.
  • Compound 5 can be converted to compound 5a under conditions such as described in fourth embodiment.
  • the compound 5a can be reacted with the compound 13 under conditions such as described in fourth embodiment to obtain compound 18b.
  • the compound of formula 5a can be added to a mixture of the compound 13 in an organic solvent, to yield the compound 18b.
  • Compound 18b is further converted to compound 19a without isolation or purification.
  • the conversion of a compound 18b to a compound 19a can be carried out under the conditions such as described in tenth embodiment.
  • the compound 19a can be converted to the compound 1 a under conditions such as described in eleventh embodiment.
  • the present application provides a process for preparing Canagliflozin (Compound 1 a) comprising the conversion of a compound 5 to Compound 18a' using compound 13.
  • Alkyl lithium includes, methyl lithium, n-propyl lithium, isopropyl lithium, cyclopropyllithium, n-butyl lithium, s-butyl lithium, t-butyl lithium, sec-amyl lithium, tert-amyl lithium, n-hexyllithium, 4-heptyllithium, cyclohexyllithium, triethylmethyllithium, 1 -methylcyclo-pentyllithium, phenyl lithium, mesityl lithium (i.e.
  • the alkyl lithium is preferably present in an amount in the range of from about 1 .0 to about 3.0 molar equivalents, or any range therein, more preferably in an amount in the range of from about 2.0 to about 2.5 molar equivalents, or any range therein, most preferably about 2.0 molar equivalents.
  • the compound 13 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein.
  • the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like; at a temperature in the range of from about 0° C. to about -78° C, or any range therein; to yield the corresponding compound 18a'.
  • organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether and the like.
  • the reaction of the compound 5 with the compound 13 can be carried out by lithiating the compound 13, followed by reacting the resultant with the compound 5.
  • the alkyl lithium can be added to a mixture of the compound 5 and the compound 13.
  • reaction of the compound 5 with the compound 13 can be carried out, wherein compound 5 is converted to compound 5a before reacting with compound 13.
  • Compound 5 can be converted to compound 5a by reacting with a complex of di(Ci- 4 alkyl) magnesium with lithium chloride such as di(sec-butyl)magnesium with lithium chloride, and the like; or a complex Ci- 4 alkyl magnesium chloride with lithium chloride or a complex of Ci- 4 alkyl magnesium bromide with lithium chloride; wherein the Ci- 4 alkyl is preferably isopropyl or sec-butyl; wherein complex is present in an amount in the range of from about 0.3 to 1 .5 molar equivalents (relative to the moles of the compound 12); in an organic solvent or mixture thereof, such as toluene, THF, hexane, pentane, MTBE, 1 ,4-dioxane, and the like; at a temperature in the range of from about ambient temperature to about -78° C, or any range therein; to yield the corresponding compound 5a.
  • the compound 5a can be reacted with the compound 13; wherein the compound 13 can be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein; in an organic solvent or mixture thereof, such as toluene, THF, hexane, pentane, MTBE, 1 ,4-dioxane, and the like; at a temperature in the range of from about ambient temperature to about -78° C, or any range therein; to yield the corresponding compound 18a'.
  • an organic solvent or mixture thereof such as toluene, THF, hexane, pentane, MTBE, 1 ,4-dioxane, and the like
  • reaction product that is isolated as a solid in the process of the present application up on further structural studies is characterized by following spectral data.
  • compound 5 can be reacted with compound 13 in presence of alkyl lithium to obtain compound 18a' in solid form.
  • the obtained solid form of compound 18a' is crystalline.
  • the said alkyl lithium includes, methyl lithium, n-propyl lithium, isopropyl lithium, cyclopropyllithium, n-butyl lithium, s-butyl lithium, t-butyl lithium, sec-amyl lithium, tert- amyl lithium, n-hexyllithium, 4-heptyllithium, cyclohexyllithium, triethylmethyllithium, 1 - methylcyclo-pentyllithium, phenyl lithium, mesityl lithium (i.e. 2,4,6-trimethylphenyl lithium), trimethylsilylmethyl lithium, triethylsilyl methyl lithium, adamantyllithium and the like.
  • the alkyl lithium is preferably present in an amount in the range of from about 1 .0 to about 3.0 molar equivalents, or any range therein, more preferably in an amount in the range of from about 2.0 to about 2.5 molar equivalents, or any range therein, most preferably about 2.0 molar equivalents.
  • the compound 13 can preferably be present in an amount in the range of from about 1 .0 to about 2.0 molar equivalents, or any range therein.
  • the reaction can be carried out in presence of organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether or mixture thereof at a temperature in the range of from about 0° C. to about -78° C, or any range therein.
  • organic solvent such as butane, pentane, THF, hexane, heptane, octane, toluene, xylene, MTBE, dioxane, diethyl ether or mixture thereof at a temperature in the range of from about 0° C. to about -78° C, or any range therein.
  • compound 18a' can be obtained in a solid form by isolation.
  • the said 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 solid form of compound 18a' may contain some amount of occluded mother liquor or higher than desired level of impurities. If desired, the obtained solid 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 obtained solid form of compound 18a' is crystalline.
  • the present application provides solid form of compound 18a' having a purity of at least about 98% as measured by HPLC (High performance liquid chromatography) method. Preferably at least about 99%, more preferably at least about 99.5%, still more preferably at least about 99.9% or most preferably at least about 99.99% as measured by a HPLC method.
  • HPLC High performance liquid chromatography
  • the present application provides crystalline form of compound 18a' having a purity of at least about 98% as measured by HPLC method. Preferably at least about 99%, more preferably at least about 99.5%, still more preferably at least about 99.9% or most preferably at least about 99.99% as measured by a HPLC method.
  • HPLC method that may be followed can be as herein described according to Figure 14.
  • the crystalline form of compound 18a' can be characterized by one or more of: (i) a DSC thermogram with an onset peak at about of 144°C; (ii) an X-ray powder diffraction pattern having peaks expressed in degrees 2 ⁇ at about 10.81 , 13.50, 18.96, 20.99, 23.73 and 30.68 ⁇ 0.2° ⁇ ; (iii) a thermogravimetric analysis showing a mass loss of 0.052%.
  • the crystalline form of compound 18a' may be further characterized by XRD peaks at about 5.40, 8.1 1 , 16.23 and 17.10 ⁇ 0.2° 2 ⁇ .
  • Figure 1 shows typical X-ray powder diffraction pattern.
  • the compound 18a' can be further purified to reduce impurities using solvent; which includes; alcohol solvent, aromatic hydrocarbon solvent, ether solvent, ketone solvent, halogenated hydrocarbon solvent, hydrocarbon solvent, nitrile solvent, polar aprotic solvent, or mixtures thereof.
  • solvent includes; alcohol solvent, aromatic hydrocarbon solvent, ether solvent, ketone solvent, halogenated hydrocarbon solvent, hydrocarbon solvent, nitrile solvent, polar aprotic solvent, or mixtures thereof.
  • the present application further provides a process for the preparation of Canagliflozin with high purity from solid form of compound 18a' with a purity of at least 98% as measured by HPLC.
  • the Canagliflozin obtained can be in any of the forms such as amorphous, crystalline or mixtures thereof.
  • the present application provides crystalline form of canagliflozin having a purity of at least about 98% as measured by HPLC method. Preferably at least about 99%, more preferably at least about 99.5%, still more preferably at least about 99.9% or most preferably at least about 99.99% as measured by a HPLC method.
  • HPLC method that may be followed can be as herein described according to Figure 15.
  • the present application further provides a process for the preparation of Canagliflozin with high purity from crystalline form of compound 18a'.
  • the Canagliflozin obtained can be in any of the forms such as amorphous, crystalline or mixtures thereof.
  • the present application further provides a process for the preparation of Canagliflozin with high purity from crystalline form of compound 18a' with a purity of at least 98% as measured by HPLC.
  • the Canagliflozin obtained can be in any of the forms such as amorphous, crystalline or mixtures thereof.
  • the compound 18a' can be converted to canagliflozin (compound 1 a) by reacting with a suitably selected Lewis acid, which includes, but not limited to, BF3.0Et2, BF3.THF, aluminum chloride, zinc chloride, iron chloride, and the like, also in the presence of a suitably selected silane reagent such as triisopropylsilane, triethylsilane, tetramethyldisiloxane, and the like; borohydrides such as sodium borohydride, potassium borohydride, lithium borohydride, sodium cyanoborohydride, potassium cyanoborohydride, lithium cyanoborohydride, sodium triacetoxyborohydride, potassium triacetoxyborohydride, also in the presence of suitable additives such as sulfuric acid, methanesulfonic acid, acetic acid, titanium chloride, zinc chloride, cobalt (II) chloride, aluminium chloride, tin chloride, nickel chloride,
  • the molar ratio of lewis acid or borohydride that can be used with respect to the compound 18a' can be easily derived by a person skilled in the art.
  • the said mole ratio can be about 0.01 , about 0.02, about 0.05, about 0.1 , about 0.2, about 0.5, about 1 .0, about 1 .5, about 2, about 3 or any other suitable mole per mole of the compound 19.
  • the conversion can take place in the presence of solvent or in the absence of a solvent.
  • the suitable solvent that can be used includes ethers such as tetrahydrofuran, dioxane, diisopropylether, diethylether, 2- methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; esters such as ethyl acetate, isopropyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or dichlorobenzene; aliphatic hydrocarbon solvents such as acetonitrile, methylcyclohexane, cyclohexane, heptane or hexane; aromatic hydrocarbon solvents such as toluene, benzene, chlorobenzene, 4-chlorotoluene, trifluorotoluene, o-xylene, m-xylene or p-x
  • compound 6 can be converted to pure Canagliflozin by first protecting compound 6 with TES (triethyl silane) and then adding slowly BF3.Etherate. Lot wise or fast addition of BF3.Etherate results in more amount of unwanted anomer. Further, unwanted anomer formation is more when water is present in the reaction system.
  • TES triethyl silane
  • slow addition or Adding slowly means the reagent may be added at a rate of for example 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.
  • Approved product of Canagliflozin which is there on the market is a-anomer. Impurities formation is more when water is present in the reaction system. For example, the reaction must not contain water more than about 0.05%. Also impurities formation is less when BF3.Etherate is added slowly.
  • the said BF3.etherate reaction can be carried out at a temperature of about -40 to about -10°C. More preferably, at a temperature of about -35 to about -20°C; most preferably at a temperature of about -30 to about -25°C.
  • BF3.Etherate addition can be carried out below about -25°C. Unwanted a-anomer formation may be more when addition takes place at a temperature of greater than about -25°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 isolation may be effected by conventional crystallization methods such as concentration to a minimum volume, cooling, adding anti-solvent or any other suitable technique.
  • Anti-solvent is a solvent other than isopropyl acetate, isopropyl alcohol or mixtures thereof in which canagliflozin is poorly soluble.
  • 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 resulting crystalline Canagliflozin 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 crystalline form of Canagliflozin obtained in the process of the present application can be characterized by X-ray powder diffraction pattern having peaks expressed in degrees 2 ⁇ at about 3.90, 15.51 , 18.86, 17.37 and 10.97 ⁇ 0.2° ⁇ .
  • the said crystalline form of Canagliflozin can be also characterized by x-ray diffraction pattern substantially as illustrated by Figure 12.
  • the said crystalline Canagliflozin also can be characterized by differential scanning thermogram (DSC) with an onset temperature of at about 90°C as illustrated by Figure 1 1 .
  • DSC differential scanning thermogram
  • the present application provides an amorphous form of Canagliflozin with a mean particle size D[4,3] of about 30 microns to about 200 microns.
  • the present application provides an amorphous form of Canagliflozin with a d(0.1 ) particle size of about 0.1 to about 30 microns, a d(0.5) particle size of about 30 microns to about 200 microns and/or a d(0.9) particle size of about 50 microns to about 400 microns.
  • the step a) of the process comprises providing a solution of Canagliflozin in a solvent.
  • suitable solvents include, but are not limited to: water; alcohols, such as, for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ketones, such as, for example, acetone, butanone, pentanone, methyl isobutyl ketone, and the like; esters, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibut
  • step b) the solution obtained in step a) is mixed with an anti-solvent in a micro mixing reactor.
  • Suitable anti solvents include, but are not limited to: water; alcohols, such as, for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, and the like; ketones, such as, for example, acetone, butanone, pentanone, methyl isobutyl ketone, and the like; esters, such as, for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl proponoate, methyl butanoate, ethyl butanoate, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl
  • step c amorphous form of Canagliflozin is isolated.
  • 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 amorphous form of Canagliflozin may contain some amount of occluded mother liquor or higher than desired level of impurities. If desired, the amorphous 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.
  • canagliflozin used as a starting material in the step a) of the process can be any physical form of Canagliflozin, such as crystalline, amorphous or their mixtures. Heating, mixing and/or kneading Canagliflozin through an extruder to result in a homogenous melt in step a).
  • the melt obtained in step a) can be forced through one or more orifices, nozzles, or moulds.
  • the extrudate can be collected by sudden cooling to room temperature or below room temperature.
  • Canagliflozin used in the step a) of thirty third embodiment includes, direct use of a reaction mixture containing Canagliflozin obtained in the course of its manufacture, if desired, after addition of one or more pharmaceutically acceptable carriers.
  • Canagliflozin can be dissolved or dispersed in a suitable solvent or mixture of solvent, either alone followed by addition of one or more pharmaceutically acceptable carriers, or in combination with one or more pharmaceutically acceptable carriers.
  • auxiliaries such as diluents or disintegrant can be added during dissolution or dispersion.
  • Canagliflozin Any physical form of Canagliflozin, such as crystalline, amorphous or their mixtures can be utilized in step a) of thirty third embodiment.
  • the present application provides a process for preparation of solid dispersion comprising amorphous canagliflozin.
  • Polymer used in step a) of the embodiment can be selected from alkylcellulose, hydroxyalkylcelluloses, hydroxyalkylalkyl cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyethylmethylcellulose(HEMC), hydroxypropylmethylcellulose succinate, hydroxypropylmethyl cellulose acetate succinate (HPMC AS), carboxymethylethylcellulose, sodium carboxymethylcellulose, pottasium carboxymethyl cellulose, cellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyacrylic acid copolymer, poly(meth)acrylic acid polymers, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl methacrylates
  • step b) Heating, mixing and/or kneading the resultant blend of step a) through an extruder to result in a homogenous melt in step b).
  • the melt obtained step b) can be forced through one or more orifices, nozzles, or moulds.
  • step d) the extrudate is collected by sudden cooling to room temperature.
  • a solution of Canagliflozin is prepared by dissolving Canagliflozin with an organic solvent.
  • the organic solvent can be selected from, for example, methanol, ethanol, isopropanol, tetrahydrofuran, acetone, acetonitrile and the like.
  • the solution is fed into a thin film dryer.
  • the bath temperature, feed rate and speed of the thin film dryer rotor can be adjusted to optimize the output.
  • the said thin film dryer can be agitated thin film dryer (ATFD).
  • the bath temperature is preferably maintained between about 46°C to about 55°C.
  • the feed rate can be set between about 6 ml/1 minute to about 8 ml/1 minute.
  • the set feed rate is preferably constant for the whole process.
  • the speed of the rotor can be set between about 1300 to about 1400 revolutions per minute.
  • the drying process is accompanied by the application of vacuum.
  • the drying process is performed at about 40°C to about 45°C and for sufficient time to effect maximum removal of the solvents and then cooled to room temperature and unloaded.
  • the resulting amorphous form can be further dried by a process as described herein above.
  • the resulting amorphous form can be converted into solid dispersion.
  • the present application provides an amorphous form of Canagliflozin showing a glass transition in modulated DSC thermogram with an onset temperature of at least about 45 °C.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising an amorphous form of Canagliflozin showing a glass transition in modulated DSC thermogram with an onset temperature of at least about 45°C and one or more pharmaceutically acceptable carriers.
  • the present application provides a process for preparing crystalline form of Canagliflozin by isolating from a solution of Canagliflozin in a solvent comprising isopropyl acetate, isopropyl alcohol or mixtures thereof with any other solvent.
  • 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 of canagliflozin 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 canagliflozin 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.
  • Canagliflozin used as a starting material in thirty eighth embodiment of the present application can be any physical form of Canagliflozin, such as crystalline, amorphous or their mixtures.
  • the step a) of the purification of 2-(4-fluorophenyl) thiophene comprises dissolving 2-(4-fluorophenyl) thiophene in an organic solvent.
  • the organic solvent is selected from polar protic or polar aprotic solvents or mixture of both. Suitable solvents which include, but are not limited to acetone, methanol, ethanol, isopropanol, DMSO, DMF, acetonitrile, tetrahydrofuran, ethylacetate and any mixtures thereof.
  • step b) of the solution obtained in step a) of the purification of 2-(4- fluorophenyl) thiophene is mixed with an anti-solvent.
  • Suitable anti solvents which include, but are not limited to: a solvent selected from water, n-hexane, diethylether, 1 ,4-dioxane or mixture of water miscible organic solvents.
  • the said mixing can be either way i.e. adding anti-solvent to the solution obtained step a) or adding the solution obtained in step a) to an anti-solvent.
  • 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.
  • 2-(4-fluorophenyl) thiophene used as a starting material in the step a) of the purification of 2-(4-fluorophenyl) thiophene can be prepared by any of the methods known in the literature or by the methods described in the present application.
  • Canagliflozin obtained in process of the present application may be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions.
  • Formulations may be in the forms of immediate release, delayed release or modified release.
  • immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems.
  • the formulation may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Formulation may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
  • Amorphous form of Canagliflozin obtained in process of the present application or a solid dispersion comprising amorphous form of Canagliflozin and one or more pharmaceutically acceptable excipients obtained in the present application may be further formulated as: solid oral dosage forms such as, but not limited to: powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions.
  • Formulations may be in the forms of immediate release, delayed release or modified release.
  • immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems.
  • the formulation may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Formulation may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.
  • PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper Ka radiation wavelength 1 .5418A.
  • DSC analysis is conducted using a Modulated Differential Scanning Calorimeter (Model-TA Instruments (Q2000) (New Castle DE 19720, USA) equipped with refrigerated cooling accessory. The temperature and heat flow was calibrated using Indium. All measurements were performed by taking 3 to 7 mg of samples encapsulated into aluminum sample pans with pierced aluminum lid. The measurements were conducted under nitrogen with a purging rate of 50 mL/min.
  • PSD analysis is carried in Malvern mastersizer-2000 by a wet method.
  • Reaction mass was further stirred for 1 hour at -75 to -78°C.
  • Methanesulphonic acid (0.76 mL, 0.01 moles)
  • methanol (16.6 mL) were mixed and this solution was added to the reaction mass at -75 to -78°C over a period of 15-20 min.
  • Temperature of the reaction mass was raised to room temperature and stirred for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 5- 10°C and aqueous NaHC0 3 solution was added to the reaction mass.
  • Reaction mass was extracted with EtOAc (30 mL X 2). Organic layers were combined and washed with brine solution (50 mL X 2).
  • reaction was quenched with Aq.NaHCO 3 solution (4.6 mL) and stirred for 30 min at 0 to 5°C. Reaction mass was concentrated under vacuum and the residue was diluted with water (1 1 mL). Reaction mass was extracted with EtOAc (30 mL X2). Organic extracts were combined, washed with water (3.2 mL). Organic layer was dried over Na2SO 4 and concentrated under reduced pressure to get compound 1 (282 mg, 75.2%) as an off-white colored solid.
  • reaction mass was stirred for 1 hour at -75 to -78°C.
  • Methanesulphonic acid (0.8 mL, 0.012 moles), methanol (16.6 imL) were mixed and this solution was added to the reaction mass at -75 to -78°C over a period of 5-10 min.
  • Temperature was raised to room temperature and stirred for 15-16 hours. The progress of the reaction was monitored by TLC.
  • reaction mass was cooled to 5 - 10 0 C. pH of the reaction mass was around 2.
  • the reaction mass was basified using aqueous NaHC0 3 solution till the pH of 8.
  • Reaction mass was extracted with EtOAc (10 mL X 2). Organic layers were combined and washed with brine solution (10 mL).
  • Reaction mass was cooled to 0-5°C and AICI 3 (20.3g, 0.025 moles) was added in to the reaction mixture and stirred for 30 minutes. Temperature of the reaction mass was raised to room temperature and for 16 hours. Reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 0 - 5°C, ice cold water (810 mL) was added with stirring in to the reaction mixture over the period of 10- 20 min. Layers were separated and organic layer was kept aside to use it further. Aqueous layer was extracted with DCM (150 mL X 2) and layers were separated. Organic layers were combined and dried over anhydrous K 2 CO 3 and filtered.
  • reaction was quenched with Aq.NaHC0 3 solution (10%, 0.72 mL mL) and stirred for 30 min at 0 to 5°C. Reaction mass was concentrated under vacuum and the residue was diluted with water (10 mL). Reaction mass was extracted with DCM (10 mL X2). Organic extracts were combined, washed with brine (5 mL). Organic layer was dried over Na 2 SO 4 and concentrated reduced pressure to get compound 1 a (16 mg).
  • Reaction mass was concentrated under reduced pressure. Reaction mass was diluted with water (10 mL) and extracted with EtOAc (2 x 15 mL). Organic extracts were combined and washed with brine solution (15 mL). Organic layer was dried over Na2SO 4 and concentrated under reduced pressure to obtain compound 16 (40 mg).
  • reaction was quenched with saturated Aq.NaHCO3 solution (5 mL) and stirred for 30 min at 0 to 5°C. Reaction mass was concentrated under vacuum and the residue was diluted with water (10 mL). Reaction mass was extracted with ethyl acetate (10 mL X2). Organic extracts were combined, washed with brine (10 mL). Organic layer was dried over Na 2 SO 4 and concentrated under reduced pressure to get crude compound 1 a. Crude compound was triturated with n-Hexane (3 x 3 mL), organic layer was decanted. Product was dried under reduced pressure to give compound 1 a (10 mg).
  • reaction was quenched with 10% ammonium chloride solution (200 mL). Layers were separated and organic layer was kept aside for further use. Aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, dried over sodium sulphate and concentrated under vacuum. The crude compound was dissolved in ethyl acetate (100 mL), 2% HCI solution (200 mL) was added and stirred overnight at 29°C. The layers were separated and organic layer was kept aside for further use. Aqueous layer was extracted with ethyl acetate (100 mL). The organic layers were combined, washed with brine, dried over sodium sulphate, filtered, and concentrated under vacuum.
  • reaction mixture was slowly warmed to -20 °C and stirred for 2 h. After the completion of the reaction as confirmed by TLC, the reaction mixture was quenched with saturated solution of sodium bicarbonate. The crude compound was extracted with EtOAc (50 ml_). The organic layer was separated, dried over Na 2 S0 4 and concentrated under reduced pressure to obtain the desired product as light yellow solid.
  • Example 28 Preparation of amorphous Canagliflozin (micro mixer)
  • Canagliflozin (6 gm) is dissolved in toluene (68 ml) at 45 °C.
  • the completely dissolved solution is mixed with n-heptane (chilled to 5°C, 680 ml) with toluene to n-heptane ratio of 1 :10 by volume using valve assisted mixer.
  • the precipitated solution is filtered and then dried to give titled compound. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 65.6 °C and an end point of 68.9 °C.
  • Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 100 °C and 105 °C. Canagliflozin hemihydrate is charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing.
  • Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate is charged at B1 and material started to collect from B4. Sample is ground with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 54.6 °C and an end point of 61.5 °C.
  • Example 31 Solid dispersion with copovidone (1 :0.5 weight ratio)
  • Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate was blended with copovidone in 1 :0.5 ratio and charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 64.6 °C and an end point of 76.6 °C.
  • Example 32 Solid dispersion with PVP K-30 (1 :0.5 weight ratio)
  • Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate was blended with PVP K-30 in 1 :0.5 ratio and charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 51 .8 °C and an end point of 59.8 °C.
  • Example 33 Solid dispersion with H PMC- AS (1 :0.5 weight ratio)
  • Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate was blended with HPMC AS in 1 :0.5 ratio and charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 58.4 °C and an end point of 68.1 °C.
  • Example 34 Solid dispersion with Eudragit (1 :0.5 weight ratio) Hot melt extruder with 4 chambers of which temperature can be independently fixed is used for extrusion. Temperature of chambers B1 (inlet), B2, B3 and B4 (outlets) are fixed at 30°C, 50°C, 105°C and 1 10°C. Canagliflozin hemihydrate was blended with Eudragit in 1 :0.5 ratio and charged at B1 and material started to collect from B4. Sample is grinded with mortar pestle or analytical testing. It has shown a glass transition in modulated DSC thermogram with an onset temperature of 53.7 °C and an end point of 61 .0 °C.
  • Example 35 Preparation of amorphous form of Canagliflozin
  • Canagliflozin (2 Kg) was dissolved in Methanol (1 1 .1 L) at 30°C under stirring. Charcoal (0.1 Kg) was added to the solution and stirred for 45 minutes. Reaction mass was filtered and washed with methanol (4 L). The filtrate was heated to 42°C and subjected to Agitated Thin Film Dryer (ATFD). The solid material was dried under vacuum at 43°C for 13 hours to provide amorphous form of Canagliflozin.
  • Charcoal 0.1 Kg
  • ATFD settings bath temperature: 48-53°C; Feeding rate: 4.2L/hour; Vacuum: 745 mm Hg and RPM: 1400. After completion of feeding, the mass was kept under vacuum (740-750 mm Hg) at 48-52°C for 15-30 minutes and then cooled to room temperature and unloaded.
  • the resulting amorphous form of Canagliflozin is micronized using Jet Mill at a mill pressure of about 3.5 kg/cm 2 and a feed pressure of about 3.0 kg/cm 2 for three times.
  • Example 36 Preparation of crystalline form of Canagliflozin
  • reaction mass After the maintenance dilute the reaction mass with water 132 (ml) and stirred for 20 minutes.
  • the reaction mass was extracted with ethyl actate (100mlx2 times) and combined the organic layers, filtered on a cellite bed and washed with ethyl actate (50ml). Combined the organic layers and dried with sodiumsulphate and evaporated to get crude title compound.
  • Example 39 Purification of 2-(4-fluorophenyl) thiophene using acetone and water Crude 2-(4-fluorophenyl) thiophene (1 g) obtained in example 1 was dissolved in acetone (4 ml) and the solution was added to water (8 ml) at 0-5oC. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.
  • Example 40 Purification of 2-(4-fluorophenyl) thiophene using methanol and water
  • Example 41 Purification of 2-(4-fluorophenyl) thiophene using IPA and water
  • Example 42 Purification of 2-(4-fluorophenyl) thiophene using ethanol and water
  • Example 43 Purification of 2-(4-fluorophenyl) thiophene using dimethylsulfoxide (DMSO) and water
  • Example 44 Purification of 2-(4-fluorophenyl) thiophene using methanol and water
  • Example 45 Purification of 2-(4-fluorophenyl) thiophene using isopropyl alcohol (IPA) and water
  • Example 47 Purification of 2-(4-fluorophenyl) thiophene using IPA and water 2-(4-fluorophenyl) thiophene (0.5 g) obtained in example 9 was dissolved in IPA (4 ml) and the solution was added to water (1 ml) at room temperature. The precipitate was filtered to give pure 2-(4-fluorophenyl) thiophene.
  • Example 48 Purification of 2-(4-fluorophenyl) thiophene using methanol and water
  • the reaction mixture was quenched with triethylamine (1 1 .70 ml) and concentrated under reduced pressure at an elevated temperature of about 50°C up to 2 to 3 volumes with respect to compound 18a'.
  • the resulting mixture was cooled to room temperature, dichloromethane (720 ml) and DM water (450 ml) were added and stirred for about 15 minutes. The layers were separated. To the organic layer, water (450 ml) was added and stirred. Again layers were separated. Organic layer was concentrated under vacuum at an elevated temperature of about 50°C.
  • dichloromethane (450 ml) was added and distilled under vacuum up to 2-3 volumes below 50°C temperature.
  • methyl tertiarybutylether (540 ml) and water (7 ml) were added followed by crystalline Canagliflozin seed (0.903 gm) were added.
  • the resulting mixture was stirred for 4-5 hours at room temperature.
  • Methyl tertiarybutylether (540 ml) was added and distilled below 60°C to 5-6 volumes.
  • methyl tertiarybutylether (540 ml) was added and distilled below 60°C to 5-6 volumes and water (7 ml) was added and stirred for 3 hours.
  • the reaction mass was filtered and washed with methyl tertiarybutylether (90 ml) to give crude Canagliflozin (65.9 gm).
  • Example 50 Preparation of amorphous form of Canagliflozin
  • ATFD parameters Bath temperature: 50-60°C; Feeding rate: 2-4 L/hour; Vacuum: About 700 mm Hg.

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Abstract

La présente invention concerne un procédé pour la préparation d'inhibiteurs de SGLT2, ainsi qu'un procédé pour la préparation de canagliflozine, la préparation d'une forme amorphe de canagliflozine et d'une dispersion solide de canagliflozine.
PCT/IB2015/059676 2014-12-17 2015-12-16 Procédé de préparation d'inhibiteurs de sglt2 WO2016098016A1 (fr)

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IN2362CH2015 2015-05-08
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017093949A1 (fr) * 2015-12-04 2017-06-08 Dr. Reddy's Laboratories Limited Canagliflozine sensiblement pure
WO2018020506A1 (fr) * 2016-07-25 2018-02-01 Natco Pharma Ltd Processus pour la préparation des formes amorphes de canagliflozine
WO2018149327A1 (fr) * 2017-02-20 2018-08-23 浙江华海药业股份有限公司 Procédé de préparation d'une forme amorphe de la canagliflozine
CN108530434A (zh) * 2017-03-03 2018-09-14 重庆医药工业研究院有限责任公司 卡格列净的杂质化合物及其制备方法
CN108912092A (zh) * 2018-08-07 2018-11-30 浙江华海致诚药业有限公司 一种卡格列净开环杂质的制备方法
US10370365B2 (en) * 2015-09-16 2019-08-06 Optimus Drugs (P) Limited Process for the preparation of Canagliflozin
CN111205265A (zh) * 2020-03-02 2020-05-29 沧州那瑞化学科技有限公司 2-(4-氟苯基)-5-[(5-溴-2-甲基苯基)甲基]噻吩的制备方法
WO2020129899A1 (fr) * 2018-12-17 2020-06-25 株式会社トクヤマ Procédé de production de dérivés de c-aryl hydroxy glycoxyde
WO2020129900A1 (fr) * 2018-12-17 2020-06-25 株式会社トクヤマ Procédé de production d'un dérivé de c-arylhydroxy glycoxyde
CN111410639A (zh) * 2020-04-14 2020-07-14 天津法莫西医药科技有限公司 一种恩格列净中间体杂质的制备方法
CN111920804A (zh) * 2020-09-10 2020-11-13 浙江诺得药业有限公司 一种卡格列净固体分散体、其制备方法及其应用
US11020412B2 (en) 2017-03-16 2021-06-01 Inventia Healthcare Limited Pharmaceutical composition comprising dapagliflozin
WO2021172955A1 (fr) * 2020-02-27 2021-09-02 주식회사 대웅제약 Intermédiaire utile pour la synthèse d'un inhibiteur de sglt et procédé de préparation d'un inhibiteur de sglt l'utilisant
WO2021176096A1 (fr) 2020-03-05 2021-09-10 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un inhibiteur du sglt2
WO2021245253A1 (fr) 2020-06-05 2021-12-09 Krka, D.D., Novo Mesto Préparation de dapagliflozine amorphe très pure
WO2022107463A1 (fr) * 2020-11-18 2022-05-27 株式会社トクヤマ Procédé de production d'un dérivé de cétone
RU2802443C1 (ru) * 2020-02-27 2023-08-29 Тэвун Фармасьютикал Ко., Лтд. Промежуточное соединение, применяемое для синтеза ингибитора sglt, и способ получения ингибитора sglt с применением указанного промежуточного соединения

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WO2013064909A2 (fr) * 2011-10-31 2013-05-10 Scinopharm Taiwan, Ltd. Formes cristallines et non cristallines d'inhibiteurs de sglt2
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
CN102115468B (zh) * 2009-12-31 2014-06-11 上海特化医药科技有限公司 一种2,5-二取代噻吩化合物的合成方法

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CN102115468B (zh) * 2009-12-31 2014-06-11 上海特化医药科技有限公司 一种2,5-二取代噻吩化合物的合成方法
WO2013064909A2 (fr) * 2011-10-31 2013-05-10 Scinopharm Taiwan, Ltd. Formes cristallines et non cristallines d'inhibiteurs de sglt2
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

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10370365B2 (en) * 2015-09-16 2019-08-06 Optimus Drugs (P) Limited Process for the preparation of Canagliflozin
WO2017093949A1 (fr) * 2015-12-04 2017-06-08 Dr. Reddy's Laboratories Limited Canagliflozine sensiblement pure
WO2018020506A1 (fr) * 2016-07-25 2018-02-01 Natco Pharma Ltd Processus pour la préparation des formes amorphes de canagliflozine
US11008357B2 (en) 2017-02-20 2021-05-18 Zhejiang Huahai Pharmaceutical Co., Ltd. (Cn) Method for preparing canagliflozin amorphous form
WO2018149327A1 (fr) * 2017-02-20 2018-08-23 浙江华海药业股份有限公司 Procédé de préparation d'une forme amorphe de la canagliflozine
CN108530434A (zh) * 2017-03-03 2018-09-14 重庆医药工业研究院有限责任公司 卡格列净的杂质化合物及其制备方法
US11660308B2 (en) 2017-03-16 2023-05-30 Inventia Healthcare Limited Pharmaceutical composition comprising dapagliflozin
US11020412B2 (en) 2017-03-16 2021-06-01 Inventia Healthcare Limited Pharmaceutical composition comprising dapagliflozin
CN108912092A (zh) * 2018-08-07 2018-11-30 浙江华海致诚药业有限公司 一种卡格列净开环杂质的制备方法
WO2020129899A1 (fr) * 2018-12-17 2020-06-25 株式会社トクヤマ Procédé de production de dérivés de c-aryl hydroxy glycoxyde
WO2020129900A1 (fr) * 2018-12-17 2020-06-25 株式会社トクヤマ Procédé de production d'un dérivé de c-arylhydroxy glycoxyde
CN115087649A (zh) * 2020-02-27 2022-09-20 株式会社大熊制药 用于合成sglt抑制剂的中间体和使用该中间体制备sglt抑制剂的方法
WO2021172955A1 (fr) * 2020-02-27 2021-09-02 주식회사 대웅제약 Intermédiaire utile pour la synthèse d'un inhibiteur de sglt et procédé de préparation d'un inhibiteur de sglt l'utilisant
KR20210109476A (ko) * 2020-02-27 2021-09-06 주식회사 대웅제약 Sglt 저해제의 합성에 유용한 중간체 및 이를 이용한 sglt 저해제의 제조 방법
CN115087649B (zh) * 2020-02-27 2024-07-05 株式会社大熊制药 用于合成sglt抑制剂的中间体和使用该中间体制备sglt抑制剂的方法
JP7442663B2 (ja) 2020-02-27 2024-03-04 デーウン ファーマシューティカル カンパニー リミテッド Ｓｇｌｔ阻害剤の合成に有用な中間体およびこれを用いたｓｇｌｔ阻害剤の製造方法
KR102572714B1 (ko) 2020-02-27 2023-08-31 주식회사 대웅제약 Sglt 저해제의 합성에 유용한 중간체 및 이를 이용한 sglt 저해제의 제조 방법
RU2802443C1 (ru) * 2020-02-27 2023-08-29 Тэвун Фармасьютикал Ко., Лтд. Промежуточное соединение, применяемое для синтеза ингибитора sglt, и способ получения ингибитора sglt с применением указанного промежуточного соединения
CN111205265A (zh) * 2020-03-02 2020-05-29 沧州那瑞化学科技有限公司 2-(4-氟苯基)-5-[(5-溴-2-甲基苯基)甲基]噻吩的制备方法
CN111205265B (zh) * 2020-03-02 2022-12-02 沧州那瑞化学科技有限公司 2-(4-氟苯基)-5-[(5-溴-2-甲基苯基)甲基]噻吩的制备方法
WO2021176096A1 (fr) 2020-03-05 2021-09-10 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un inhibiteur du sglt2
CN111410639A (zh) * 2020-04-14 2020-07-14 天津法莫西医药科技有限公司 一种恩格列净中间体杂质的制备方法
WO2021245253A1 (fr) 2020-06-05 2021-12-09 Krka, D.D., Novo Mesto Préparation de dapagliflozine amorphe très pure
CN111920804A (zh) * 2020-09-10 2020-11-13 浙江诺得药业有限公司 一种卡格列净固体分散体、其制备方法及其应用
WO2022107463A1 (fr) * 2020-11-18 2022-05-27 株式会社トクヤマ Procédé de production d'un dérivé de cétone

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