WO2019193572A1 - Procédé amélioré pour la préparation d'étabonate de rémogliflozine ou d'un sel, solvate, hydrate pharmaceutiquement acceptable de celui-ci - Google Patents

Procédé amélioré pour la préparation d'étabonate de rémogliflozine ou d'un sel, solvate, hydrate pharmaceutiquement acceptable de celui-ci Download PDF

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Publication number
WO2019193572A1
WO2019193572A1 PCT/IB2019/052830 IB2019052830W WO2019193572A1 WO 2019193572 A1 WO2019193572 A1 WO 2019193572A1 IB 2019052830 W IB2019052830 W IB 2019052830W WO 2019193572 A1 WO2019193572 A1 WO 2019193572A1
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WIPO (PCT)
Prior art keywords
formula
solvate
isopropyl alcohol
remogliflozin etabonate
remogliflozin
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Application number
PCT/IB2019/052830
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English (en)
Inventor
Veerabhadra SWAMY
Shekhar Bhaskar Bhirud
Ranjeet Nair
Eknath KHEMNAR
Sanjay Kadam
Jitendra THORAT
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Glenmark Pharmaceuticals Limited
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Publication date
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Publication of WO2019193572A1 publication Critical patent/WO2019193572A1/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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Definitions

  • the present invention relates to an improved process for the preparation of
  • Remogliflozin of formula (I) its prodrug Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate hydrate thereof.
  • the present invention further relates to an improved process for preparation of Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate hydrate thereof, through formation of isopropyl alcohol solvate of Remogliflozin etabonate.
  • the present invention further relates to isopropyl solvate of Remogliflozin etabonate and process for preparation thereof.
  • Remogliflozin etabonate is a pro-drug of Remogliflozin, the active entity that inhibits the sodium dependent glucose transporter 2 (SGLT2).
  • Remogliflozin etabonate is chemically known as 5-methyl-4-[4-(l-methylethoxy)benzyl]-l-(l- methylethyl)-lH-pyrazol-3-yl 6-0- (ethoxycarbonyl)-P -D-glucopyranosid.
  • Remogliflozin etabonate is known to exhibit a strong inhibitory action for SGLT2 and is proposed for treatment of diabetic patients.
  • isopropyl alcohol solvate of Remogliflozin etabonate According to another aspect of present invention, there is provided isopropyl alcohol solvate of Remogliflozin etabonate.
  • isopropyl alcohol solvate of Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram.
  • an isopropyl alcohol solvate of Remogliflozin etabonate characterized by powder X-ray diffraction (PXRD) pattern.
  • thermogravimetric analysis curve TGA
  • Figure 1 depicts differential scanning calorimetric (DSC) thermogram of isopropyl alcohol solvate of Remogliflozin etabonate
  • Figure 2 depicts powder X-ray diffraction (PXRD) pattern of isopropyl alcohol solvate of Remogliflozin etabonate
  • Figure 3 depicts TG thermogram of isopropyl alcohol solvate of Remogliflozin etabonate
  • hydrate means a compound, in which water molecule/s is/are chemically bound to another compound or molecule or element.
  • the term“hydrate” used herein is inclusive of hemihydrate.
  • Remogliflozin includes Remogliflozin free base and is used interchangeably throughout the disclosure.
  • salts or“pharmaceutically acceptable salt” as used herein, is intended to mean those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
  • crystalline as used herein, means having a regularly repeating arrangement of molecules or external face planes. Unless stated otherwise, percentages stated throughout this specification are weight/weight (w/w) percentages.
  • room temperature unless stated otherwise, essentially means temperature in range of 25-27 °C.
  • the present invention relates to an improved process for preparation of Remogliflozin etabonate of formula (II)
  • Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof comprises reacting Remogliflozin of formula (I) with ethyl haloformate.
  • ethyl haloformate is ethylchloro formate.
  • the reaction may be carried out in the presence of base and suitable solvent.
  • Suitable base may be organic or inorganic base.
  • the organic base used in the step (i) of the process may be selected from 2,6-lutidine, pyridine, 2,4.6 trimethyl pyridine, triethylamine, diisopropylamine, diisopropylethylamine or mixture thereof.
  • the suitable solvent used in step (i) may be selected from the group consisting of toluene, xylene, benzene and acetone.
  • said reaction may be carried out at a suitable temperature.
  • the reaction may be carried out at temperature ranging from 0 to -20° C.
  • the reaction mixture may be stirred for suitable period of time till the completion of the reaction.
  • the product may be isolated by the conventional technique such as extraction using suitable solvent or mixture of solvents.
  • the residue may be directly used in the next step.
  • step (ii) Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof of step (i) is converted into isopropyl alcohol solvate of Remogliflozin etabonate.
  • the conversion of Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof to its isopropyl solvate may be carried out by mixing Remogliflozin etabonate or pharmaceutically acceptable salt, solvate, hydrate thereof by treatment with isopropyl alcohol or mixture of isopropyl alcohol and a suitable solvent.
  • a suitable solvent may be a hydrocarbon solvent.
  • the step (i) product is treated with isopropyl alcohol at suitable temperature.
  • the reaction mass may be stirred for a suitable period of time.
  • the solid may be collected by known techniques such as filtration.
  • the product of step (i) is mixed with a mixture of isopropyl alcohol and n- heptane.
  • the reaction mixture may be stirred at a suitable temperature for a suitable time.
  • the mixture may be stirred at room temperature or at an elevated temperature such as 50° to 90° C.
  • the reaction mass may be, if required, gradually cooled to room temperature.
  • the solid may be collected by known techniques such as filtration and dried. In another embodiment, the solid may be further crystallized from isopropyl alcohol.
  • step (iii) isopropyl alcohol solvate of Remogliflozin etabonate is converted to Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate hydrate thereof.
  • the obtained Remogliflozin etabonate of step (iii) is in a hydrate form.
  • Remogliflozin etabonate obtained in step (iii) is Remogliflozin etabonate hemihydrate.
  • isopropyl alcohol solvate of Remogliflozin etabonate of step (ii) is treated with a mixture of solvents such as mixture of water and a suitable solvent.
  • isopropyl alcohol solvate of Remogliflozin etabonate of step (ii) is treated with a mixture of solvents such as mixture of water and acetonitrile.
  • the reaction mass may be stirred at a suitable temperature for a suitable period of time.
  • the reaction mass may be filtered to remove undesired impurities.
  • the solution may be further treated with suitable amount of water and stirred.
  • the obtained solid may be washed and collected by known techniques such as filtration.
  • the present process for preparation of Remogliflozin etabonate or pharmaceutically acceptable salt, solvate or hydrate thereof is advantageous as it allows Remogliflozin etabonate to be prepared in high yield and good quality via isopropyl alcohol solvate of Remogliflozin etabonate.
  • the preparation of isopropyl alcohol solvate of Remogliflozin etabonate ensures removal of maximum impurities. Additional merits of the process for preparation of Remogliflozin etabonate or pharmaceutically acceptable salt, solvate or hydrate thereof are high reproducibility and scalability.
  • Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof obtained is substantially pure.
  • the term“substantially pure” as used herein includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example by HPLC.
  • the present invention relates to substantially pure
  • the present invention relates to substantially pure Remogliflozin etabonate hemihydrate having purity greater than 98% as determined by HPLC.
  • the present invention relates to substantially pure
  • the present invention relates to substantially pure Remogliflozin etabonate hemihydrate having purity greater than 99% as determined by HPLC.
  • the present invention relates to substantially pure
  • the present invention relates to substantially pure Remogliflozin etabonate hemihydrate having purity greater than 99.5% as determined by HPLC.
  • the present invention relates to substantially pure Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof having purity greater than 99.9% as determined by HPLC. According to another embodiment, the present invention relates to substantially pure Remogliflozin etabonate hemihydrate having purity greater than 99.9% as determined by HPLC.
  • the substantially pure Remogliflozin etabonate of formula (II) is stable hemihydrate form of Remogliflozin etabonate.
  • an isopropyl alcohol solvate of Remogliflozin etabonate there is provided an isopropyl alcohol solvate of Remogliflozin etabonate.
  • an isopropyl alcohol solvate of Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram, a powder X-ray diffraction (PXRD) pattern or a thermogravimetric analysis curve (TGA).
  • the isopropyl alcohol solvate of Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram represented by figure 1.
  • Remogliflozin etabonate characterized by differential scanning calorimetric (DSC) thermogram having endotherm at about 9l.7l°C and l09.39°C.
  • the isopropyl alcohol solvate of Remogliflozin etabonate characterized by an X-ray powder diffraction pattern represented in figure 2.
  • the isopropyl alcohol solvate of Remogliflozin etabonate characterized by an X-ray powder diffraction pattern comprising reflections at 6.74° , 9.42°, 11.70°, 18.24°, 19.41°, 19.79° and 22.13° ⁇ 0.2° 2Q.
  • the isopropyl alcohol solvate of Remogliflozin etabonate characterized by an X-ray powder diffraction pattern comprising reflections at 6.74 °, 9.42 °, 11.06°, 11.70 °, 13.40°, 13. 80°, 15.88°, 17.01°, 18.24°, 18.79°, 19.09°, 19.41°, 19.79°, 22.13°, 22.53° and 27.99° ⁇ 0.2° 2Q.
  • thermogravimetric analysis curve (TGA) represented in figure 3.
  • step (i) Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof is mixed with isopropyl alcohol or mixture of isopropyl alcohol and suitable solvent.
  • a suitable solvent may be a hydrocarbon solvent.
  • Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof is mixed with isopropyl alcohol at suitable temperature.
  • the reaction mass may be stirred for a suitable period of time.
  • the solid may be collected by known techniques such as filtration.
  • the obtained sold may be optionally further washed with isopropyl alcohol.
  • Remogliflozin etabonate of formula (II) or pharmaceutically acceptable salt, solvate, hydrate thereof is mixed with a mixture of isopropyl alcohol and suitable solvent such as n- heptane.
  • the reaction mixture may be stirred at a suitable temperature for a suitable time. In an embodiment, the mixture may be stirred at room temperature or at an elevated temperature such as 50° to 90° C.
  • the reaction mass may be, if required, gradually cooled to room temperature.
  • the solid may be collected by known techniques such as filtration. In another embodiment, the solid may be further crystallized from isopropyl alcohol. In another embodiment, the solid may be further washed with isopropyl alcohol.
  • the isopropyl alcohol solvate of Remogliflozin etabonate obtained is substantially pure.
  • substantially pure includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example by HPLC.
  • step (a) 4-(hydromethyl)phenol is alkylated with 2- halopropane such as 2-chloropropoane, 2-bromopropane and 2-iodopropane.
  • 2- halopropane such as 2-chloropropoane, 2-bromopropane and 2-iodopropane.
  • the chlorinating agent used in step (b) include, but is not limited to, oxalyl chloride, thionyl chloride, phosphorous trichloride, phosphorous pentachloride, phosphorous oxychloride.
  • the preferred chlorinating agent is oxalyl chloride or phosphorous oxychloride.
  • the base used in the step (a) and (c) are selected from organic or inorganic base.
  • the organic base is selected from, but not limited to, triethylamine (TEA), N,N- diethylisopropylamine, N,N-diisopropylethylamine (DIPEA), diethylamine, tripropylamine and trioctylamine.
  • TAA triethylamine
  • DIPEA N,N- diethylisopropylethylamine
  • DIPEA diethylamine
  • tripropylamine diethylamine
  • trioctylamine Preferably N,N-diisopropylethylamine (DIPEA) is used.
  • the inorganic base is selected from, but not limited to, alkali metal alkoxide such as potassium tert. butoxide, an alkali metal hydride such as sodium hydride or potassium hydride or alkali metal carbonates such as
  • step (c) is carried out in presence of an alkali metal halide.
  • the alkali metal halide used in step (c) is selected from, but not limited to, a group consisting of lithium bromide, lithium chloride, sodium iodide and potassium iodide.
  • the suitable solvents used in steps (a), (b), (c) or (d) is selected from polar or non-polar solvents.
  • the polar solvent is selected from C 1 -C 5 alcohols such as methanol, ethanol, n- propanol, isopropyl alcohol and the like, N,N-dimethylformamide, acetonitrile, dichloromethane, ethyl acetate, tetrahydrofuran and the like.
  • the non-polar solvent is selected from C 5-12 aromatic hydrocarbons such as toluene, xylene and the like, C 2-8 ethers or mixtures thereof.
  • step (d) provides reaction of compound of formula (V) with hydrazine, preferably hydrazine hydrate, to obtain a cyclized compound of formula (VII).
  • step (e) illustrates the tosylation or mesylation of compound of formula (VII) to give sulfonated compounds.
  • Tosylation of compound of formula (VII) can be carried out by reaction with tosyl chloride in presence of a base and solvent. The reaction may be carried out at a suitable temperature such as l0-30°C.
  • Suitable solvents include, but not limited to, N,N-dimethylformamide, acetonitrile, dichloromethane, and ethyl acetate .
  • Bases which may be utilized include, but are not limited to, cesium carbonate, potassium carbonate, pyridine, and triethylamine.
  • Mesylation of the compound of formula (VII) may be performed by reaction with methanesulfonyl chloride or methanesulfonic anhydride optionally in the presence of a base in a suitable solvent.
  • suitable solvents include, but are not limited to, N,N-dimethylformamide, acetonitrile, and n-methyl pyrrolidinone.
  • Bases which may be utilized include, but are not limited to, pyridine, triethylamine and lithium hydroxide. Accordingly, in one embodiment, the tosylation or mesylation may be carried out in the presence of a base, preferably pyridine.
  • the compound of formula (VIII) is alkylated and then is desulfonated to form a compound of formula (IX).
  • the alkylation of compound of formula (VIII) is carried out by reaction with alkyl halide, such as 2-chloropropoane, 2-bromopropane and 2-iodopropane, in presence of a base and solvent.
  • the base used is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, cesium carbonate, potassium carbonate, sodium tert-butoxide, lithium tert-butoxide, lithium carbonate, and sodium carbonate, 1 ,8- diazabicyclo [5.4.0 ]undec-7-ene, triethylamine, pyridine, preferably lithium hydroxide is used.
  • Suitable solvents include N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, dichloromethane and the like, preferably N-methyl-2- pyrrolidone is used.
  • Desulfonation is carried out using a base such as sodium hydroxide or potassium hydroxide to obtain compound of formula (IX).
  • step (f) the alkylation reaction of step (f) is quenched with base such as triethanol amine prior to desulfonation step.
  • step (g) compound of formula (IX) is reacted with protected glucose derivative in presence of base in suitable solvent. After the completion of the reaction, the residue is hydrolyzed in presence of base such as sodium hydroxide to cleave the protecting group and obtain Remogliflozin of formula (I).
  • the protecting group may be selected from, but are not limited to, acetyl group, pivaloyl group, benzoyl group or a benzyl group.
  • the base may be selected from organic or inorganic base.
  • inorganic bases which may be utilized include, but are not limited to, sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide and the like.
  • the solvent may be selected from, but are not limited to toluene, acetone, 2-butanone, methyl-isobutyl ketone, ethanol, methanol, isopropanol, butanol, tert-butanol, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether, and dichloromethane
  • the present process for preparation of Remogliflozin of Formula (I) provides substantially pure Remogliflozin of Formula (I).
  • the term“substantially pure” as used herein includes reference to purity of, or greater than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example, by HPLC.
  • DSC Differential scanning calorimetry thermogram was measured by a Differential scanning calorimeter (DSC 822, Mettler Toledo) having temperature range of 30 to 350 °C with heating rate of l0°C/min.
  • X-ray powder diffraction method (XPRD) pattern was collected on Phillips X-ray diffractometer model XPERT -PRO (PANalytical) Detector Xcelerator.
  • the reaction mixture was neutralized by the addition of sodium hydroxide and 300 ml of methanol. The mixture was maintained for 1-2 hours and after the completion of the reaction, the pH was adjusted to 7-8 by adding dilute hydrochloric acid. The reaction mixture was heated to 60-65 °C and maintained for 20-30 mins. The reaction mass was cooled to room temperature and stirred for about 18 hours. The product was collected by filtration. Wet cake obtained was dried at about 60-65 °C for 10 hours to obtain about 23 g of 5-methyl- l-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]- l,2-dihydro-3H-pyrazol-3-one.
  • reaction mass was concentrated to get oily mass of 5-methyl- l-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-lH-pyrazol-3-yl 2,3,4,6-tetra-0-acetyl-P-D- glucopyranoside.
  • the obtained oily mass as such was taken for the next stage.
  • reaction mass was then extracted with ethyl acetate and the ethyl acetate layer obtained was washed with 5% brine solution and then concentrated to residual mass.
  • residual mass was added tert-butanol, ethyl acetate and n-hexane mixture and stirred for 15 hours to get slurry.
  • the slurry was filtered and washed with n-hexane.
  • the product was dried to get 150 g of Remogliflozin free base.
  • the solid was isolated from residue by using mixture of 450 ml of ethanol 450 ml and 450 ml of n-heptane. The obtained solid was further taken in 750 ml of isopropyl alcohol and the reaction mass was stirred at room temperature. The obtained solid was fileted and dried under vacuum at 45°C to give 53 g of isopropyl solvate of Remogliflozin Etabonate.
  • Isopropyl alcohol solvate of Remogliflozin etabonate obtained in example 16 was subjected to conversion to stable hemihydrate Remogliflozin etabonate by dissolving in 1: 1 acetonitrile and water mixture followed by addition of 18 volumes of water.
  • the hemihydrate Remogliflozin etabonate obtained was dried at 40 °C for 10 hours to get 8 lg (0.6 w/w) of final product having HPLC purity of > 99%.
  • the obtained solid was taken in 1080 ml of isopropyl alcohol and the reaction mass was heated to 75-80 °C. The reaction mass was cooled to room temperature. The solid, Remogliflozin etabonate isopropyl solvate was collected by filtration and dried.
  • Remogliflozin etabonate isopropyl solvate was mixed with 75 ml water and 75 ml acetonitrile. The reaction mass was stirred at room temperature for 30 minutes. The reaction mass was filtered. The clear filtrate was taken in a flask and 1350 ml of water was added. The reaction mass was stirred at room temperature for 8-10 hours. The obtained solid was filtered, washed with 270 ml water and dried to obtain 97.2 g of Remogliflozin Etabonate Hemihydrate.

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Abstract

La présente invention concerne un procédé amélioré pour la préparation de rémogliflozine, d'étabonate de rémogliflozine ou d'un sel, solvate, hydrate pharmaceutiquement acceptable de ceux-ci. La présente invention concerne un procédé amélioré pour la préparation d'étabonate de rémogliflozine ou d'un sel, solvate, hydrate pharmaceutiquement acceptable de celui-ci par la formation d'un solvate d'alcool isopropylique d'étabonate de rémogliflozine.
PCT/IB2019/052830 2018-04-05 2019-04-05 Procédé amélioré pour la préparation d'étabonate de rémogliflozine ou d'un sel, solvate, hydrate pharmaceutiquement acceptable de celui-ci WO2019193572A1 (fr)

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IN201821013037 2018-04-05

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7393838B2 (en) * 2000-12-28 2008-07-01 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives and use thereof in medicines
WO2010127067A1 (fr) * 2009-04-30 2010-11-04 Glaxosmithkline Llc Processus chimique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7393838B2 (en) * 2000-12-28 2008-07-01 Kissei Pharmaceutical Co., Ltd. Glucopyranosyloxypyrazole derivatives and use thereof in medicines
WO2010127067A1 (fr) * 2009-04-30 2010-11-04 Glaxosmithkline Llc Processus chimique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BILLOT ET AL.: "Efficient Purification of an Active Pharmaceutical Ingredient via Cocrystallization: From Thermodynamics to Scale-Up", ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 17, no. 3, 2012, pages 505 - 511, XP055643191 *
MASAHIRO KOBAYASHI ET AL.: "O-Glycosylation of 4-(Substituted benzyl)-1,2-dihydro-3H-pyrazol-3-one Derivatives with 2,3,4,6-Tetra-O-acyl--D-glucopyranosyl Bromide via Nl-Acetylation of the Pyrazole Ring", CHEM. PHARM. BULL., vol. 64, no. 7, 2016, pages 1009 - 1018, XP055643189 *

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