WO2016189463A1 - Ertugliflozin co-crystals and process for their preparation - Google Patents

Ertugliflozin co-crystals and process for their preparation Download PDF

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Publication number
WO2016189463A1
WO2016189463A1 PCT/IB2016/053042 IB2016053042W WO2016189463A1 WO 2016189463 A1 WO2016189463 A1 WO 2016189463A1 IB 2016053042 W IB2016053042 W IB 2016053042W WO 2016189463 A1 WO2016189463 A1 WO 2016189463A1
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ertugliflozin
proline
crystal
process according
solvent
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French (fr)
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Ramkinkar SANTRA
Bala Krishna Reddy BHOGALA
Chandra Has Khanduri
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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Priority to EP16799455.7A priority Critical patent/EP3303345A4/en
Priority to US15/576,452 priority patent/US10294239B2/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401—Proline; Derivatives thereof, e.g. captopril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • 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
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to processes for the preparation of an ertugliflozin-L- pyroglutamic acid (1 : 1) co-crystal and ertugliflozin-L-proline (1 : 1) co-crystal.
  • the present invention further relates to an ertugliflozin-L-proline (1 :2) co-crystal, processes for its preparation, and its use for the treatment of type 2 diabetes mellitus.
  • Ertugliflozin chemically is (lS,2S,3S,4R,5S)-5-(4 duoiO-3-(4- ethoxybenzyl)phenyl)-l-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, represented by Formula I.
  • Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus.
  • U.S. Patent No. 8,080,580 discloses processes for the preparation of ertugliflozin and its conversion to ertugliflozin-L-proline (1 : 1) co-crystal and ertugliflozin-L- pyroglutamic acid (1 : 1) co-crystal in solvents such as alcohol or aqueous alcohol. It also discloses the use of excess of L-proline and L-pyroglutamic acid.
  • PCT Publication No. WO 2014/159151 discloses a process for the preparation of ertugliflozin and its conversion to an ertugliflozin-L-pyroglutamic acid (1: 1) co-crystal using excess L-pyroglutamic acid.
  • the present invention relates to processes for the preparation of an ertugliflozin-L- pyroglutamic acid (1 : 1) co-crystal and ertugliflozin-L-proline (1 : 1) co-crystal.
  • the present invention further relates to an ertugliflozin-L-proline (1 :2) co-crystal, processes for its preparation, and its use for the treatment of type 2 diabetes mellitus.
  • Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of an ertugliflozin-L- proline (1 :2) co-crystal.
  • XRPD X-Ray Powder Diffraction
  • Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of an ertugliflozin-L-proline (1 :2) co-crystal.
  • DSC Differential Scanning Calorimetry
  • Figure 3 depicts a Thermogravimetric Analysis (TGA) thermogram of an ertugliflozin-L- proline (1 :2) co-crystal.
  • TGA Thermogravimetric Analysis
  • ambient temperature refers to any value which lies within the range between 20°C and 30°C.
  • contacting refers to bringing two or more components together by dissolving, mixing, suspending, blending, slurrying, or stirring.
  • co-crystal refers to a stoichiometric multi component system comprising an active pharmaceutical ingredient (API) and a pharmaceutical co- crystal former, wherein the API and the pharmaceutical co-crystal former are connected by non-covalent interactions.
  • API active pharmaceutical ingredient
  • co-crystal former refers to compounds which can form intermolecular interactions with an API and co-crystallize with it.
  • solvent includes, for example, saturated or unsaturated hydrocarbons, alcohols, ethers, esters, halogenated hydrocarbons, carboxylic acids, ketones, amides, sulphoxides, water, or mixtures thereof.
  • anhydrous solvent includes, for example, saturated or unsaturated hydrocarbons, alcohols, ethers, esters, halogenated hydrocarbons, carboxylic acids, ketones, amides, sulphoxides, or mixtures thereof.
  • saturated or unsaturated hydrocarbons include benzene, toluene, cyclohexane, and xylenes.
  • alcohols include methanol, ethanol, 1-propanol, 1- butanol, 2-butanol, and tertiary alcohols having from one to six carbon atoms.
  • ethers include diethyl ether, ethyl methyl ether, methyl tertiary butyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
  • esters include ethyl acetate, methyl acetate, isopropyl acetate, and tertiary butyl acetate.
  • halogenated hydrocarbons examples include dichloromethane and chloroform.
  • carboxylic acids examples include formic acid, acetic acid, and propionic acid.
  • ketones include acetone, 2-butanone, diethyl ketone, ethyl methyl ketone, and methyl iso-butyl ketone.
  • amides include NN-dimethylformamide and N,N- dimethylacetamide.
  • sulphoxides include dimethyl sulphoxide and diethyl sulphoxide.
  • a first aspect of the present invention provides a process for the preparation of an ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal of Formula Ic,
  • the process comprises contacting ertugliflozin with L-pyroglutamic acid in the presence of a solvent, wherein the amount of L-pyroglutamic acid is about 1 mole equivalent to about 1.5 mole equivalents with respect to ertugliflozin.
  • Ertugliflozin used as the starting material can be prepared by methods known in the art, for example, as in U.S. Patent No. 8,080,580.
  • the solvent is selected from the group comprising water, ethyl acetate, isopropyl acetate, 2-butanone, methyl isobutyl ketone, and methyl tertiary butyl ether.
  • the contacting of the ertugliflozin with the L- pyroglutamic acid is carried out at ambient temperature.
  • the amount of L-pyroglutamic acid is about 1 mole equivalent to about 1.1 mole equivalents with respect to ertugliflozin.
  • the ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the ertugliflozin-L- pyroglutamic acid (1 : 1) co-crystal may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • a second aspect of the present invention provides a process for the preparation of an ertugliflozin-L-proline (1 : 1) co-crystal of Formula lb,
  • the process comprises contacting ertugliflozin with L-proline in the presence of a solvent, wherein the amount of L-proline is about 1 mole equivalent to about 1.5 mole equivalents with respect to ertugliflozin.
  • Ertugliflozin used as the starting material can be prepared by methods known in the art, for example, as in U.S. Patent No. 8,080,580.
  • the solvent is ethyl acetate.
  • the contacting of the ertugliflozin with the L- proline is carried out at ambient temperature.
  • the amount of L-proline is about 1 mole equivalent to about 1.1 mole equivalents with respect to ertugliflozin.
  • the ertugliflozin-L-proline (1 : 1) co-crystal may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the ertugliflozin-L-proline (1: 1) co-crystal may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • a third aspect of the present invention provides an ertugliflozin-L-proline (1 :2) co- crystal of Formula la.
  • the ertugliflozin-L-proline (1 :2) co-crystal is characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.
  • XRPD X-ray powder diffraction
  • the ertugliflozin-L-proline (1 :2) co-crystal is characterized by an XRPD having interplanar spacing (d) values at about 27.3, 5.5, 4.8, 4.7, and 4.2 A.
  • the ertugliflozin-L-proline (1 :2) co-crystal is further characterized by an XRPD having additional interplanar spacing (d) values at about 13.7, 5.1, 4.4, 3.8, 3.5, and 2.8 A.
  • the ertugliflozin-L-proline (1:2) co- crystal is characterized by an XRPD having characteristic peak values at about 3.2, 16.2, 18.4, 18.9, and 21.4 ⁇ 0.2° 2 ⁇ .
  • the ertugliflozin-L-proline (1 :2) co-crystal is further characterized by an XRPD having additional characteristic peak values at about 6.5, 17.4, 20.4, 23.5, 25.5, and 31.6 ⁇ 0.2° 2 ⁇ .
  • Table 1 provides the 2 ⁇ values, the corresponding d-spacing values (A), and the relative intensity of the ertugliflozin-L-proline (1 :2) co-crystal.
  • the ertugliflozin-L-proline (1 :2) co-crystal is characterized by a differential scanning calorimetric (DSC) thermogram having endothermic peaks at about 148°C and 236°C, as depicted in Figure 2.
  • the ertugliflozin-L-proline (1 :2) co-crystal is characterized by a thermogravimetric analysis (TGA) thermogram as depicted in Figure 3.
  • DSC differential scanning calorimetric
  • TGA thermogravimetric analysis
  • a fourth aspect of the present invention provides a process for the preparation of an ertugliflozin-L-proline (1 :2) co-crystal of Formula la,
  • process comprises contacting ertugliflozin with L-proline in the presence of an anhydrous solvent.
  • Ertugliflozin used as the starting material can be prepared by methods known in the art, for example, as in U.S. Patent No. 8,080,580.
  • the anhydrous solvent is selected from the group comprising 2- butanone, ethyl acetate, and a mixture of ethanol and methyl tertiary butyl ether.
  • the contacting of ertugliflozin with L-proline is carried out at ambient temperature.
  • the amount of L-proline is about 0.5 mole equivalent to about 5 mole equivalents with respect to ertugliflozin.
  • the amount of L-proline is about 0.8 mole equivalent to about 2 mole equivalents with respect to ertugliflozin.
  • the water content of the anhydrous solvent is not more than 0.15%.
  • the water content of the anhydrous solvent is not more than 0.1%.
  • the ertugliflozin-L-proline (1 :2) co-crystal may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the ertugliflozin-L-proline (1 :2) co-crystal may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
  • a fifth aspect of the present invention provides a pharmaceutical composition comprising an ertugliflozin-L-proline (1 :2) co-crystal and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • a sixth aspect of the present invention provides the use of an ertugliflozin-L- proline (1 :2) co-crystal for the treatment of type 2 diabetes mellitus.
  • the XRPD of the samples were determined by using Instrument: PANalytical ® ;
  • the DSC of the samples were determined using a Mettler-Toledo ® 821e. Data collection parameters: Scanning rate: 10°C/min; Temperature: 30°C to 300°C.
  • the TGA of the samples were determined by using a TA ® Q500 between 30°C and
  • Ertugliflozin (0.5 g) was added to a solution of L-pyroglutamic acid (2.2 mL; L- pyroglutamic acid (0.563 g) dissolved in water (2.73 mL)), and then the solution was stirred for 1.5 hours at 25°C to 30°C. Water (1.5 mL) was added to the reaction mixture, and then the mixture was stirred for 1 hour. The obtained solid was filtered, and then dried under vacuum at 40°C for 6 hours.
  • Ertugliflozin (0.225 g) and L-pyroglutamic acid (0.067 g) were added to ethyl acetate (3 mL), and then the mixture was stirred for 3 hours at 25 °C to 30°C.
  • Ethyl acetate (2 mL) was added to the reaction mixture, and the mixture was stirred for 4 hours.
  • the obtained solid was filtered, and then washed with ethyl acetate (3 mL). The solid was dried under vacuum at 25°C to 30°C for 1 hour, and then at 40°C for 5 hours.
  • Ertugliflozin (0.225 g) and L-pyroglutamic acid (0.067 g) were added to isopropyl acetate (3 mL), and then the mixture was stirred for 3 hours at 25°C to 30°C.
  • Isopropyl acetate (2 mL) was added to the reaction mixture, and the mixture was stirred for 4 hours.
  • the obtained solid was filtered, and then washed with isopropyl acetate (4 mL). The solid was dried under vacuum at 25 °C to 30°C for 1 hour, and then at 40°C for 5 hours.
  • Ertugliflozin (0.225 g) and L-pyroglutamic acid (0.067 g) were added to methyl isobutyl ketone (3 mL), and then the mixture was stirred for 3 hours at 25°C to 30°C.
  • Methyl isobutyl ketone (2 mL) was added to the reaction mixture, and the mixture was stirred for 4 hours.
  • the obtained solid was filtered, and then washed with methyl isobutyl ketone (4 mL). The solid was dried under vacuum at 25°C to 30°C for 1 hour, and then at 40°C for 5 hours.
  • Ertugliflozin (0.756 g) and L-proline monohydrate (0.4 g) were added to ethanol (4 mL), and then the mixture was heated in a water bath to 70°C. The solution was cooled to 25°C to 30°C. Methyl tertiary butyl ether (30 mL) was added in three lots (10 mL each), and the mixture was stirred for 6 hours at 25°C to 30°C to obtain a solid. The solid so obtained was filtered under nitrogen atmosphere. The solid was washed with methyl tertiary butyl ether (20 mL), and then dried under vacuum at 25 °C to 30°C for 4 hours, and then at 40°C for 6 hours.
  • Ertugliflozin (0.75 g) and L-proline (0.393 g) were added to 2-butanone (9 mL) at 25 °C to 30°C, and then the mixture was stirred for 30 minutes to occur precipitation. The mixture was stirred for 5 hours at 25°C to 30°C to obtain a solid. The solid so obtained was filtered under nitrogen atmosphere. The solid was washed with 2-butanone (5 mL), and then dried under vacuum at 25°C to 30°C for 4 hours, and then at 40°C for 6 hours.
  • Ertugliflozin (0.25 g) and L-proline monohydrate (0.152 g) were added to ethyl acetate (3.5 mL, water content ⁇ 0.06%), and then the mixture was stirred for 6 hours at 25°C to 30°C. The mixture was filtered, and then dried under vacuum at 25°C to 30°C.
  • Example 10 Preparation of ertugliflozin-L-proline (1 :2) co-crystal Ertugliflozin (0.25 g) and L-proline monohydrate (0.067 g) were added to ethanol (1 mL), and then the mixture was heated in a water bath to 70°C. The solution was cooled to 25 °C to 30°C. Methyl tertiary butyl ether (10 mL) was added, and the mixture was stirred for 5 hours at 25°C to 30°C to obtain a solid. The solid so obtained was filtered under nitrogen atmosphere. The solid was dried under vacuum at 25°C to 30°C for 6 hours, and then at 40°C for 4 hours.
  • Ertugliflozin (0.25 g) and L-proline monohydrate (0.201 g) were added to ethanol (1.5 mL), and then the mixture was heated in a water bath to 70°C. The solution was cooled to 25°C to 30°C. Methyl tertiary butyl ether (10 mL) was added, and the mixture was stirred for 5 hours at 25°C to 30°C to obtain a solid. The solid so obtained was filtered under nitrogen atmosphere. The solid was dried under vacuum at 25°C to 30°C for 6 hours, and then at 40°C for 4 hours.

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Abstract

The present invention relates to processes for the preparation of an ertugliflozin-L- pyroglutamic acid (1:1) and co-crystal ertugliflozin-L-proline (1:1) co-crystal. The present invention further relates to an ertugliflozin-L-proline (1:2) co-crystal, processes for its preparation, and its use for the treatment of type 2 diabetes mellitus.

Description

ERTUGLIFLOZIN CO-CRYSTALS AND PROCESS FOR THEIR
PREPARATION
Field of the Invention
The present invention relates to processes for the preparation of an ertugliflozin-L- pyroglutamic acid (1 : 1) co-crystal and ertugliflozin-L-proline (1 : 1) co-crystal. The present invention further relates to an ertugliflozin-L-proline (1 :2) co-crystal, processes for its preparation, and its use for the treatment of type 2 diabetes mellitus.
Background of the Invention
Ertugliflozin chemically is (lS,2S,3S,4R,5S)-5-(4 duoiO-3-(4- ethoxybenzyl)phenyl)-l-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, represented by Formula I.
Figure imgf000002_0001
Formula I
Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus.
U.S. Patent No. 8,080,580 discloses processes for the preparation of ertugliflozin and its conversion to ertugliflozin-L-proline (1 : 1) co-crystal and ertugliflozin-L- pyroglutamic acid (1 : 1) co-crystal in solvents such as alcohol or aqueous alcohol. It also discloses the use of excess of L-proline and L-pyroglutamic acid.
PCT Publication No. WO 2014/159151 discloses a process for the preparation of ertugliflozin and its conversion to an ertugliflozin-L-pyroglutamic acid (1: 1) co-crystal using excess L-pyroglutamic acid.
There is a need in the art for providing a process for the preparation of ertugliflozin co-crystals which is commercially viable and economical. Further, there is a need in the art for providing an ertugliflozin co-crystal with desirable physico-chemical properties such as solubility, rate of dissolution of the drug, chemical stability, melting point, and hygroscopicity. Summary of the Invention
The present invention relates to processes for the preparation of an ertugliflozin-L- pyroglutamic acid (1 : 1) co-crystal and ertugliflozin-L-proline (1 : 1) co-crystal. The present invention further relates to an ertugliflozin-L-proline (1 :2) co-crystal, processes for its preparation, and its use for the treatment of type 2 diabetes mellitus.
Brief Description of the Drawings
Figure 1 depicts an X-Ray Powder Diffraction (XRPD) pattern of an ertugliflozin-L- proline (1 :2) co-crystal.
Figure 2 depicts a Differential Scanning Calorimetry (DSC) thermogram of an ertugliflozin-L-proline (1 :2) co-crystal.
Figure 3 depicts a Thermogravimetric Analysis (TGA) thermogram of an ertugliflozin-L- proline (1 :2) co-crystal.
Detailed Description of the Invention
Various embodiments and variants of the present invention are described hereinafter.
The term "about," as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term "ambient temperature," as used herein, refers to any value which lies within the range between 20°C and 30°C.
The term "contacting," as used herein, refers to bringing two or more components together by dissolving, mixing, suspending, blending, slurrying, or stirring.
The term "co-crystal," as used herein, refers to a stoichiometric multi component system comprising an active pharmaceutical ingredient (API) and a pharmaceutical co- crystal former, wherein the API and the pharmaceutical co-crystal former are connected by non-covalent interactions.
The term "co-crystal former," as used herein, refers to compounds which can form intermolecular interactions with an API and co-crystallize with it.
The term "solvent," as used herein, includes, for example, saturated or unsaturated hydrocarbons, alcohols, ethers, esters, halogenated hydrocarbons, carboxylic acids, ketones, amides, sulphoxides, water, or mixtures thereof. The term "anhydrous solvent," as used herein, includes, for example, saturated or unsaturated hydrocarbons, alcohols, ethers, esters, halogenated hydrocarbons, carboxylic acids, ketones, amides, sulphoxides, or mixtures thereof.
Examples of saturated or unsaturated hydrocarbons include benzene, toluene, cyclohexane, and xylenes. Examples of alcohols include methanol, ethanol, 1-propanol, 1- butanol, 2-butanol, and tertiary alcohols having from one to six carbon atoms. Examples of ethers include diethyl ether, ethyl methyl ether, methyl tertiary butyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane. Examples of esters include ethyl acetate, methyl acetate, isopropyl acetate, and tertiary butyl acetate.
Examples of halogenated hydrocarbons include dichloromethane and chloroform.
Examples of carboxylic acids include formic acid, acetic acid, and propionic acid.
Examples of ketones include acetone, 2-butanone, diethyl ketone, ethyl methyl ketone, and methyl iso-butyl ketone. Examples of amides include NN-dimethylformamide and N,N- dimethylacetamide. Examples of sulphoxides include dimethyl sulphoxide and diethyl sulphoxide.
A first aspect of the present invention provides a process for the preparation of an ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal of Formula Ic,
Figure imgf000004_0001
Formula Ic
wherein the process comprises contacting ertugliflozin with L-pyroglutamic acid in the presence of a solvent, wherein the amount of L-pyroglutamic acid is about 1 mole equivalent to about 1.5 mole equivalents with respect to ertugliflozin.
Ertugliflozin used as the starting material can be prepared by methods known in the art, for example, as in U.S. Patent No. 8,080,580.
The solvent is selected from the group comprising water, ethyl acetate, isopropyl acetate, 2-butanone, methyl isobutyl ketone, and methyl tertiary butyl ether.
In one embodiment of this aspect, the contacting of the ertugliflozin with the L- pyroglutamic acid is carried out at ambient temperature. Preferably, the amount of L-pyroglutamic acid is about 1 mole equivalent to about 1.1 mole equivalents with respect to ertugliflozin.
The ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The ertugliflozin-L- pyroglutamic acid (1 : 1) co-crystal may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
A second aspect of the present invention provides a process for the preparation of an ertugliflozin-L-proline (1 : 1) co-crystal of Formula lb,
Figure imgf000005_0001
Formula lb
wherein the process comprises contacting ertugliflozin with L-proline in the presence of a solvent, wherein the amount of L-proline is about 1 mole equivalent to about 1.5 mole equivalents with respect to ertugliflozin.
Ertugliflozin used as the starting material can be prepared by methods known in the art, for example, as in U.S. Patent No. 8,080,580.
Preferably, the solvent is ethyl acetate.
In one embodiment of this aspect, the contacting of the ertugliflozin with the L- proline is carried out at ambient temperature.
Preferably, the amount of L-proline is about 1 mole equivalent to about 1.1 mole equivalents with respect to ertugliflozin.
The ertugliflozin-L-proline (1 : 1) co-crystal may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The ertugliflozin-L-proline (1: 1) co-crystal may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying.
A third aspect of the present invention provides an ertugliflozin-L-proline (1 :2) co- crystal of Formula la.
Figure imgf000006_0001
Formula la
In one embodiment of this aspect, the ertugliflozin-L-proline (1 :2) co-crystal is characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.
In another embodiment of this aspect, the ertugliflozin-L-proline (1 :2) co-crystal is characterized by an XRPD having interplanar spacing (d) values at about 27.3, 5.5, 4.8, 4.7, and 4.2 A. The ertugliflozin-L-proline (1 :2) co-crystal is further characterized by an XRPD having additional interplanar spacing (d) values at about 13.7, 5.1, 4.4, 3.8, 3.5, and 2.8 A.
In yet another embodiment of this aspect, the ertugliflozin-L-proline (1:2) co- crystal is characterized by an XRPD having characteristic peak values at about 3.2, 16.2, 18.4, 18.9, and 21.4 ±0.2° 2Θ. The ertugliflozin-L-proline (1 :2) co-crystal is further characterized by an XRPD having additional characteristic peak values at about 6.5, 17.4, 20.4, 23.5, 25.5, and 31.6 ±0.2° 2Θ.
Table 1 provides the 2Θ values, the corresponding d-spacing values (A), and the relative intensity of the ertugliflozin-L-proline (1 :2) co-crystal.
Table 1
Figure imgf000007_0001
In another embodiment of this aspect, the ertugliflozin-L-proline (1 :2) co-crystal is characterized by a differential scanning calorimetric (DSC) thermogram having endothermic peaks at about 148°C and 236°C, as depicted in Figure 2. In another embodiment of this aspect, the ertugliflozin-L-proline (1 :2) co-crystal is characterized by a thermogravimetric analysis (TGA) thermogram as depicted in Figure 3.
A fourth aspect of the present invention provides a process for the preparation of an ertugliflozin-L-proline (1 :2) co-crystal of Formula la,
Figure imgf000008_0001
Formula la
wherein the process comprises contacting ertugliflozin with L-proline in the presence of an anhydrous solvent.
Ertugliflozin used as the starting material can be prepared by methods known in the art, for example, as in U.S. Patent No. 8,080,580.
Preferably, the anhydrous solvent is selected from the group comprising 2- butanone, ethyl acetate, and a mixture of ethanol and methyl tertiary butyl ether.
In one embodiment of this aspect, the contacting of ertugliflozin with L-proline is carried out at ambient temperature.
In another embodiment of this aspect, the amount of L-proline is about 0.5 mole equivalent to about 5 mole equivalents with respect to ertugliflozin. Preferably, the amount of L-proline is about 0.8 mole equivalent to about 2 mole equivalents with respect to ertugliflozin.
In yet another embodiment of this aspect, the water content of the anhydrous solvent is not more than 0.15%. Preferably, the water content of the anhydrous solvent is not more than 0.1%.
The ertugliflozin-L-proline (1 :2) co-crystal may be isolated by employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The ertugliflozin-L-proline (1 :2) co-crystal may further be dried using conventional techniques, for example, drying, drying under vacuum, spray drying, freeze drying, air drying, or agitated thin film drying. A fifth aspect of the present invention provides a pharmaceutical composition comprising an ertugliflozin-L-proline (1 :2) co-crystal and one or more pharmaceutically acceptable carriers, diluents, or excipients.
A sixth aspect of the present invention provides the use of an ertugliflozin-L- proline (1 :2) co-crystal for the treatment of type 2 diabetes mellitus.
While the present invention has been described in terms of its specific aspects, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Methods:
The XRPD of the samples were determined by using Instrument: PANalytical®;
Model: X'pert PRO; Detector: X'celerator®; Step size: 0.02; Range: 3-40 degree 2 theta; CuKa radiation at 45kV and 40 mA.
The DSC of the samples were determined using a Mettler-Toledo® 821e. Data collection parameters: Scanning rate: 10°C/min; Temperature: 30°C to 300°C.
The TGA of the samples were determined by using a TA® Q500 between 30°C and
300°C at 10°C/min scan rate.
The following examples are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.
EXAMPLES
Example 1 : Preparation of ertugliflozin-L-proline (1 : 1) co-crystal
Ertugliflozin (0.5 g) and L-proline (0.131 g) were added to ethyl acetate (3 mL, water content ~ 0.18%), and then the mixture was stirred for 1 hour at 25°C to 30°C. Ethyl acetate (2 mL) was added to the reaction mixture, and the mixture was stirred for 16 hours. The obtained solid was filtered, and then dried under vacuum at 25°C to 30°C. Yield: 0.61 g
Example 2: Preparation of ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal
Ertugliflozin (0.5 g) was added to a solution of L-pyroglutamic acid (2.2 mL; L- pyroglutamic acid (0.563 g) dissolved in water (2.73 mL)), and then the solution was stirred for 1.5 hours at 25°C to 30°C. Water (1.5 mL) was added to the reaction mixture, and then the mixture was stirred for 1 hour. The obtained solid was filtered, and then dried under vacuum at 40°C for 6 hours.
Yield: 0.472 g
Example 3 : Preparation of ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal
Ertugliflozin (0.225 g) and L-pyroglutamic acid (0.067 g) were added to ethyl acetate (3 mL), and then the mixture was stirred for 3 hours at 25 °C to 30°C. Ethyl acetate (2 mL) was added to the reaction mixture, and the mixture was stirred for 4 hours. The obtained solid was filtered, and then washed with ethyl acetate (3 mL). The solid was dried under vacuum at 25°C to 30°C for 1 hour, and then at 40°C for 5 hours.
Yield: 0.2 g
Example 4: Preparation of ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal
Ertugliflozin (0.225 g) and L-pyroglutamic acid (0.067 g) were added to isopropyl acetate (3 mL), and then the mixture was stirred for 3 hours at 25°C to 30°C. Isopropyl acetate (2 mL) was added to the reaction mixture, and the mixture was stirred for 4 hours. The obtained solid was filtered, and then washed with isopropyl acetate (4 mL). The solid was dried under vacuum at 25 °C to 30°C for 1 hour, and then at 40°C for 5 hours.
Yield: 0.22 g
Example 5 : Preparation of ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal
Ertugliflozin (0.225 g) and L-pyroglutamic acid (0.067 g) were added to 2- butanone (3 mL), and then the mixture was stirred for 3 hours at 25 °C to 30°C. 2- Butanone (2 mL) was added to the reaction mixture, and the mixture was stirred for 4 hours. The obtained solid was filtered, and then washed with 2-butanone (3 mL). The solid was dried under vacuum at 25°C to 30°C for 1 hour, and then at 40°C for 5 hours.
Yield: 0.14 g
Example 6: Preparation of ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal
Ertugliflozin (0.225 g) and L-pyroglutamic acid (0.067 g) were added to methyl isobutyl ketone (3 mL), and then the mixture was stirred for 3 hours at 25°C to 30°C. Methyl isobutyl ketone (2 mL) was added to the reaction mixture, and the mixture was stirred for 4 hours. The obtained solid was filtered, and then washed with methyl isobutyl ketone (4 mL). The solid was dried under vacuum at 25°C to 30°C for 1 hour, and then at 40°C for 5 hours.
Yield: 0.23 g
Example 7: Preparation of ertugliflozin-L-proline (1 :2) co-crystal
Ertugliflozin (0.756 g) and L-proline monohydrate (0.4 g) were added to ethanol (4 mL), and then the mixture was heated in a water bath to 70°C. The solution was cooled to 25°C to 30°C. Methyl tertiary butyl ether (30 mL) was added in three lots (10 mL each), and the mixture was stirred for 6 hours at 25°C to 30°C to obtain a solid. The solid so obtained was filtered under nitrogen atmosphere. The solid was washed with methyl tertiary butyl ether (20 mL), and then dried under vacuum at 25 °C to 30°C for 4 hours, and then at 40°C for 6 hours.
Yield: 0.862 g
*H NMR (400 MHz, MeOD): δ ppm 1.35-1.39 (t, 3H), 1.96-2.02 (m, 4H), 2.12-2.15 (m, 2H), 2.28-2.30 (m, 2H), 3.22-3.23 (m, 2H), 3.25-3.33 (m, 2H), 3.54-3.61 (m, 4H), 3.64- 3.67 (m, 2H), 3.68-3.86 (m, 4H), 3.95-4.03 (m, 2H), 4.04-4.16 (d, 1H), 6.80-6.82 (d, 2H), 7.09-7.11 (d, 2H), 7.37-7.46 (m, 2H), 7.47 (s, 1H).
Example 8: Preparation of ertugliflozin-L-proline (1 :2) co-crystal
Ertugliflozin (0.75 g) and L-proline (0.393 g) were added to 2-butanone (9 mL) at 25 °C to 30°C, and then the mixture was stirred for 30 minutes to occur precipitation. The mixture was stirred for 5 hours at 25°C to 30°C to obtain a solid. The solid so obtained was filtered under nitrogen atmosphere. The solid was washed with 2-butanone (5 mL), and then dried under vacuum at 25°C to 30°C for 4 hours, and then at 40°C for 6 hours.
Yield: 0.918 g
Example 9: Preparation of ertugliflozin-L-proline (1 :2) co-crystal
Ertugliflozin (0.25 g) and L-proline monohydrate (0.152 g) were added to ethyl acetate (3.5 mL, water content < 0.06%), and then the mixture was stirred for 6 hours at 25°C to 30°C. The mixture was filtered, and then dried under vacuum at 25°C to 30°C.
Yield: 0.295 g
Example 10: Preparation of ertugliflozin-L-proline (1 :2) co-crystal Ertugliflozin (0.25 g) and L-proline monohydrate (0.067 g) were added to ethanol (1 mL), and then the mixture was heated in a water bath to 70°C. The solution was cooled to 25 °C to 30°C. Methyl tertiary butyl ether (10 mL) was added, and the mixture was stirred for 5 hours at 25°C to 30°C to obtain a solid. The solid so obtained was filtered under nitrogen atmosphere. The solid was dried under vacuum at 25°C to 30°C for 6 hours, and then at 40°C for 4 hours.
Yield: 0.19 g
Example 11 : Preparation of ertugliflozin-L-proline (1 :2) co-crystal
Ertugliflozin (0.25 g) and L-proline monohydrate (0.201 g) were added to ethanol (1.5 mL), and then the mixture was heated in a water bath to 70°C. The solution was cooled to 25°C to 30°C. Methyl tertiary butyl ether (10 mL) was added, and the mixture was stirred for 5 hours at 25°C to 30°C to obtain a solid. The solid so obtained was filtered under nitrogen atmosphere. The solid was dried under vacuum at 25°C to 30°C for 6 hours, and then at 40°C for 4 hours.
Yield: 0.33 g

Claims

We claim:
1. A process for the preparation of an ertugliflozin-L-pyroglutamic acid (1 : 1) co-crystal of Formula Ic,
Figure imgf000013_0001
Formula Ic
wherein the process comprises contacting ertugliflozin with L-pyroglutamic acid in the presence of a solvent, wherein the amount of L-pyroglutamic acid is about 1 mole equivalent to about 1.5 mole equivalents with respect to ertugliflozin.
2. The process according to claim 1, wherein the solvent is selected from the group
comprising water, ethyl acetate, isopropyl acetate, 2-butanone, and methyl isobutyl ketone.
3. The process according to claim 1, wherein the contacting of ertugliflozin with L- pyroglutamic acid in the presence of a solvent is carried out at ambient temperature. 4. The process according to claim 1, wherein the amount of L-pyroglutamic acid is about 1 mole equivalent to about 1.1 mole equivalents with respect to ertugliflozin.
5. A process for the preparation of an ertugliflozin-L-proline (1 : 1) co-crystal of Formula lb,
Figure imgf000013_0002
Formula lb
wherein the process comprises contacting ertugliflozin with L-proline in the presence of a solvent, wherein the amount of L-proline is about 1 mole equivalent to about 1.5 mole equivalents with respect to ertugliflozin.
6. The process according to claim 5, wherein the solvent is ethyl acetate. The process according to claim 5, wherein the contacting of ertugliflozin with L- proline in the presence of a solvent is carried out at ambient temperature.
The process according to claim 5, wherein the amount of L-proline is about 1 mole equivalent to about 1.1 mole equivalent with respect to ertugliflozin.
Ertugliflozin-L-proline (1:2) co-crystal of Formula la.
Figure imgf000014_0001
Formula la
10. The ertugliflozin-L-proline (1 :2) co-crystal according to claim 9, characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1.
11. The ertugliflozin-L-proline (1 :2) co-crystal according to claim 9, characterized by an XRPD having interplanar spacing (d) values at about 27.3, 5.8, 4.8, 4.7, and 4.2 A.
12. The ertugliflozin-L-proline (1 :2) co-crystal according to claim 11, characterized by an XRPD having additional interplanar spacing (d) values at about 13.7, 5.1, 4.4, 3.8, 3.5, and 2.8 A.
13. The ertugliflozin-L-proline (1 :2) co-crystal according to claim 9, characterized by an XRPD having characteristic peak values at about 3.2, 16.2, 18.4, 18.9, and 21.4 ±0.2° 2Θ.
14. The ertugliflozin-L-proline (1 :2) co-crystal according to claim 13, further
characterized by an XRPD having additional characteristic peak values at about 6.5, 17.4, 20.4, 23.5, 25.5, and 31.6 ±0.2° 2Θ.
15. The ertugliflozin-L-proline (1 :2) co-crystal according to claim 9, characterized by a differential scanning calorimetric (DSC) thermogram having endothermic peaks at about 148°C and 236°C as depicted in Figure 2.
16. The ertugliflozin-L-proline (1 :2) co-crystal according to claim 9, characterized by a thermogravimetric analysis (TGA) thermogram as depicted in Figure 3.
17. A process for the preparation of an ertugliflozin-L-proline (1 :2) co-crystal of Formula la,
Figure imgf000015_0001
wherein the process comprises contacting ertugliflozin with L-proline in the presence of an anhydrous solvent.
18. The process according to claim 17, wherein the anhydrous solvent is selected from the group comprising 2-butanone, ethyl acetate, and a mixture of ethanol and methyl tertiary butyl ether.
19. The process according to claim 17, wherein the amount of L-proline for contacting with ertugliflozin is about 0.5 mole equivalent to about 5 mole equivalents with respect to ertugliflozin.
20. The process according to claim 19, wherein the amount of L-proline is about 0.8 mole equivalent to about 2 mole equivalents with respect to ertugliflozin.
21. The process according to claim 17, wherein the water content of the anhydrous solvent is not more than 0.15%.
22. The process according to claim 21, wherein the water content of the anhydrous solvent is not more than 0.1%.
23. A pharmaceutical composition comprising an ertugliflozin-L-proline (1 :2) co-crystal and one or more pharmaceutically acceptable carriers, diluents, or excipients.
24. The use of an ertugliflozin-L-proline (1 :2) co-crystal for the treatment of type 2
diabetes mellitus.
PCT/IB2016/053042 2015-05-25 2016-05-24 Ertugliflozin co-crystals and process for their preparation Ceased WO2016189463A1 (en)

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