WO2017134606A1 - Crystalline form of {(1r,2s,3s,4r,5s)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl}methyl acetate - Google Patents

Crystalline form of {(1r,2s,3s,4r,5s)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl}methyl acetate Download PDF

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WO2017134606A1
WO2017134606A1 PCT/IB2017/050581 IB2017050581W WO2017134606A1 WO 2017134606 A1 WO2017134606 A1 WO 2017134606A1 IB 2017050581 W IB2017050581 W IB 2017050581W WO 2017134606 A1 WO2017134606 A1 WO 2017134606A1
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trihydroxy
dioxabicyclo
oct
phenyl
chloro
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PCT/IB2017/050581
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French (fr)
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Israr ALI
Ashwini Kumar Kapoor
Asok Nath
Mohan Prasad
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Sun Pharmaceutical Industries Limited
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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
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
    • C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
    • C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms

Definitions

  • the present invention relates to a crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5-[4- chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1- yl ⁇ methyl acetate of Formula II and
  • the present invention further relates to a process for the conversion of a crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl ⁇ methyl acetate of Formula II to ertugliflozin.
  • Ertugliflozin chemically is (15 , ,25 , ,35 , ,4R,55)-5-(4-chloiO-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 provides 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.
  • the discovery of new forms of a compound, in particular a drug substance, may improve desirable processing properties of the drug, such as ease of handling, storage stability, and ease of purification.
  • the present invention provides a crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5-[4- chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1- yl ⁇ methyl acetate of Formula II.
  • Figure 1 depicts an X-ray powder diffraction (XRPD) pattern of crystalline Form B of ⁇ (li?,2,S * ,3 1 S * ,4i?,5 1 S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl ⁇ methyl acetate of Formula II prepared as per Example 1.
  • XRPD X-ray powder diffraction
  • Figure 2 depicts an XRPD pattern of crystalline Form B of ⁇ (lR,2S,3S,4R,5S)-5- [4-chloro-3-(4-ethoxybenzyl)phenyl] -2,3 ,4-trihydroxy-6, 8-dioxabicyclo [3.2.1 ]oct- 1 - yl ⁇ methyl acetate of Formula II prepared as per Example 2.
  • Figure 3 depicts an XRPD pattern of crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5- [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl ⁇ methyl acetate of Formula II prepared as per Example 3.
  • Figure 4 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form B of ⁇ (li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl ⁇ methyl acetate of Formula II prepared as per Example 1.
  • DSC Differential Scanning Calorimetry
  • Figure 5 depicts a DSC thermogram of crystalline Form B of ⁇ (l i ⁇ S ⁇ S ⁇ -S- [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl ⁇ methyl acetate of Formula II prepared as per Example 2.
  • Figure 6 depicts a DSC thermogram of crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5- [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl ⁇ methyl acetate of Formula II prepared as per Example 3.
  • treating refers to bringing two or more components together by dissolving, mixing, suspending, blending, slurrying, or stirring.
  • solvent includes water, esters, alkanols,
  • halogenated hydrocarbons ketones, ethers, polar aprotic solvents, saturated or unsaturated hydrocarbons, and mixtures thereof.
  • esters include ethyl acetate, ⁇ -propyl acetate, isopropyl acetate, and «-butyl acetate.
  • alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms.
  • alkanols include methanol, ethanol, «-propanol, isopropanol, butanol, 2-methoxyethanol, and 2- ethoxyethanol.
  • halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane.
  • ketones examples include acetone, 2- butanone, diethyl ketone, ethyl methyl ketone, and methyl isobutyl ketone.
  • Exampli of ethers include diethyl ether, ethyl methyl ether, methyl tertiary butyl ether,
  • diisopropyl ether diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
  • polar aprotic solvents examples include N,N-dimethylformamide, NN- dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
  • saturated or unsaturated hydrocarbons examples include benzene, toluene,
  • a first aspect of the present invention provides a crystalline Form B of
  • the crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5- [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl ⁇ methyl acetate of Formula II is characterized by an X-ray powder diffraction (XRPD) pattern having characteristic peak values at 5.6, 14.7, 16.8, 20.7, and 24.4 ⁇ 0.2° 2 ⁇ .
  • XRPD X-ray powder diffraction
  • the crystalline Form B of ⁇ (l i ⁇ S ⁇ ? ⁇ )- 5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl ⁇ methyl acetate of Formula II is further characterized by an XRPD pattern having characteristic peak values at 11.0, 12.0, 13.2, 13.9, 17.4, 18.9, 19.4, 22.5, 23.5, 28.0, and 29.4 ⁇ 0.2° 2 ⁇ .
  • the crystalline Form B of ⁇ (l i ⁇ S ⁇ ? ⁇ )- 5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl ⁇ methyl acetate of Formula II is characterized by an XRPD pattern substantially as depicted in Figure 1, Figure 2, or Figure 3.
  • Table 1 provides the 2 ⁇ values, the corresponding d-spacing values (A), and the relative intensity of the crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl ⁇ methyl acetate of Formula II prepared as per Example 1.
  • Table 2 provides the 2 ⁇ values, the corresponding d-spacing values (A), and the relative intensity of the crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl ⁇ methyl acetate of Formula II prepared as per Example 2.
  • Table 3 provides the 2 ⁇ values, the corresponding d-spacing values (A), and the relative intensity of the crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl ⁇ methyl acetate of Formula II prepared as per Example 3.
  • the crystalline Form B of ⁇ ( ⁇ , ⁇ ) ⁇ - [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl ⁇ methyl acetate of Formula II is characterized by a differential scanning calorimetric (DSC) thermogram having an endothermic peak at about 171°C.
  • DSC differential scanning calorimetric
  • the crystalline Form B of ⁇ (l i ⁇ S ⁇ ? ⁇ )- 5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl ⁇ methyl acetate of Formula II is characterized by a DSC thermogram substantially as depicted in Figure 4, Figure 5, or Figure 6.
  • a second aspect of the present invention provides a process for the preparation of a crystalline Form B of ⁇ (li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl ⁇ methyl acetate of Formula II,
  • the present invention provides a process for the preparation of the crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl ⁇ methyl acetate of Formula II comprising the steps of:
  • step b) stirring the reaction mixture of step a) to obtain a solid;
  • the alcohol solvent is selected from the group comprising primary, secondary, and tertiary alcohols having from one to six carbon atoms. More preferably, the alcohol solvent is selected from the group comprising methanol, ethanol, «-propanol, isopropanol, butanol, 2-methoxy ethanol, and 2-ethoxy ethanol.
  • Step a) includes dissolving ⁇ (1 ⁇ 2S,3S,4R,5S)-5-[4-cMoro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1-yl ⁇ methyl acetate of Formula II in an alcohol solvent at a temperature of about 25°C to about 80°C to obtain a clear solution.
  • Step b) includes cooling the solution to about 5°C to about 25 °C, and then stirring at a temperature of about 5°C to about 25°C for about 45 minutes to about 90 minutes to obtain a solid.
  • Step c) of isolating the crystalline Form B of ⁇ (lR,25 , ,35 , ,4R,55)-5-[4-chloro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1-yl ⁇ methyl acetate of Formula II includes employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization.
  • the crystalline Form B of ⁇ (li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl ⁇ methyl acetate of Formula II may further be dried using conventional techniques, for example, drying, drying under reduced pressure, spray drying, freeze drying, air drying, or agitated thin film drying.
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1-yl ⁇ methyl acetate of Formula II and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • a fourth aspect of the present invention provides the use of a crystalline Form B of ⁇ (li?,2,S * ,3 1 S * ,4i?,5 1 S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl ⁇ methyl acetate of Formula II for the treatment of type 2 diabetes mellitus.
  • a fifth aspect of the present invention provides a process comprising converting a crystalline Form B of ⁇ (li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl ⁇ methyl acetate of Formula II to ertugliflozin.
  • the conversion of the crystalline Form B of ⁇ (li?,2,S * ,3 1 S * ,4i?,5 1 S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl ⁇ methyl acetate of Formula II to ertugliflozin may be carried out using deacetylating agents.
  • the deacetylating agent is sodium methoxide.
  • the conversion of the crystalline Form B of ⁇ ( ⁇ R,2S,3S,4R,5S)-5 -[4-chloro-3 -(4-ethoxybenzyl)phenyl] -2,3 ,4-trihydroxy-6, 8- dioxabicyclo[3.2. l]oct-l-yl ⁇ methyl acetate of Formula II to ertugliflozin may be carried by methods known in the art, for example, PCT Publication No. WO 2014/159151.
  • XRPD patterns of the samples were recorded using a PANalytical ® X'pert PRO with X'celerator ® as the detector, 0.02 as step size, and 3-40° 2 ⁇ as range, using CuKa radiation.
  • Example 1 Preparation of a crystalline Form B of ⁇ (Ti?.2 ⁇ S'.3iS'.4i?.5iS')-5-r4-chloro-3-(4- ethoxybenzyl)phenyll-2.3.4-trihydroxy-6.8-dioxabicvclor3.2. Hoct-l-yl ⁇ methyl acetate of Formula II
  • Example 2 Preparation of a crystalline Form B of UlR.2S,3SAR.5S)-5- ⁇ 4-c loro-3-(4- ethoxybenzvnphenyll-2.3.4-trihvdroxy-6.8-dioxabicvclor3.2. Hoct-l-yl ⁇ methyl acetate of Formula II
  • Example 3 Preparation of a crystalline Form B of (lR.2S,3SAR.5S)-5- ⁇ 4-c loro-3-(4- ethoxybenzyl)phenyll-2.3.4-trihydroxy-6.8-dioxabicvclor3.2. Hoct-l-yl ⁇ methyl acetate of Formula II

Abstract

The present invention relates to a crystalline Form B of {(1 R,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxybenzylphenyl]- 2,3,4-trihydroxy- 6,8-dioxabicyclo [3.2. 1]oct-1-yl}methyl acetate of Formula (II) and a process for its preparation. The present invention further relates to a process for the conversion of a crystalline Form B of {(1 R,2S,3S,4R,5S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy -6,8-dioxabicyclo[3.2.1]oct-1-yl}methyl acetate of Formula II to Ertugliflozin.

Description

CRYSTALLINE FORM OF {(li?,2£,3£,4i?,5£)-5-[4-CHLORO-3-(4- ETHOXYBENZYL)PHENYL]-2,3,4-TRIHYDROXY-6,8- DIOXABICYCLO[3.2.1]OCT-l-YL}METHYL ACETATE
Field of the Invention
The present invention relates to a crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4- chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1- yl} methyl acetate of Formula II and
Figure imgf000002_0001
Formula II
a process for its preparation. The present invention further relates to a process for the conversion of a crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl} methyl acetate of Formula II to ertugliflozin.
Background of the Invention
Ertugliflozin chemically is (15,,25,,35,,4R,55)-5-(4-chloiO-3-(4- ethoxybenzyl)phenyl)-l-hydroxymethyl-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol, represented by Formula I.
Figure imgf000002_0002
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 provides 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.
U.S. Patent No. 8,669,380 provides a process for the preparation of
{(li?,2,S*,31S*,4i?,51S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate which involves purification by flash chromatography over silica gel. The present inventors on repeating the experiment found that {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate was obtained as an oil.
PCT Publication No. WO 2014/159151 provides a crystalline form of
{ ( \R,2S,3S,4R,5S)-5 -[4-chloro-3 -(4-ethoxybenzyl)phenyl] -2,3 ,4-trihydroxy-6, 8- dioxabicyclo[3.2. l]oct-l-yl} methyl acetate having an X-ray powder diffraction pattern (CuKa radiation, wavelength of 1.54056 A) comprising 2-theta values of 5.8±0.2, 11.6±0.2, 16.0±0.2, 16.6±0.2, and 21.6±0.2.
The discovery of new forms of a compound, in particular a drug substance, may improve desirable processing properties of the drug, such as ease of handling, storage stability, and ease of purification.
Summary of the Invention
The present invention provides a crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4- chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1- yl} methyl acetate of Formula II.
Figure imgf000003_0001
Formula II
Brief Description of the Drawings
Figure 1 depicts an X-ray powder diffraction (XRPD) pattern of crystalline Form B of {(li?,2,S*,31S*,4i?,51S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II prepared as per Example 1. Figure 2 depicts an XRPD pattern of crystalline Form B of {(lR,2S,3S,4R,5S)-5- [4-chloro-3-(4-ethoxybenzyl)phenyl] -2,3 ,4-trihydroxy-6, 8-dioxabicyclo [3.2.1 ]oct- 1 - yl} methyl acetate of Formula II prepared as per Example 2.
Figure 3 depicts an XRPD pattern of crystalline Form B of {(\R,2S,3S,4R,5S)-5- [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl}methyl acetate of Formula II prepared as per Example 3.
Figure 4 depicts a Differential Scanning Calorimetry (DSC) thermogram of crystalline Form B of {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II prepared as per Example 1.
Figure 5 depicts a DSC thermogram of crystalline Form B of {(l i^^S^^^S^-S- [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl}methyl acetate of Formula II prepared as per Example 2.
Figure 6 depicts a DSC thermogram of crystalline Form B of {(\R,2S,3S,4R,5S)-5- [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl}methyl acetate of Formula II prepared as per Example 3.
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 "treating," as used herein, refers to bringing two or more components together by dissolving, mixing, suspending, blending, slurrying, or stirring.
The term "solvent," as used herein, includes water, esters, alkanols,
halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, saturated or unsaturated hydrocarbons, and mixtures thereof.
Examples of esters include ethyl acetate, ^-propyl acetate, isopropyl acetate, and «-butyl acetate. Examples of alkanols include those primary, secondary, and tertiary alcohols having from one to six carbon atoms. Examples of alkanols include methanol, ethanol, «-propanol, isopropanol, butanol, 2-methoxyethanol, and 2- ethoxyethanol. Examples of halogenated hydrocarbons include dichloromethane, chloroform, and 1,2-dichloroethane. Examples of ketones include acetone, 2- butanone, diethyl ketone, ethyl methyl ketone, and methyl isobutyl ketone. Exampli of ethers include diethyl ether, ethyl methyl ether, methyl tertiary butyl ether,
diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, and 1,4-dioxane.
Examples of polar aprotic solvents include N,N-dimethylformamide, NN- dimethylacetamide, dimethylsulphoxide, acetonitrile, and N-methylpyrrolidone.
Examples of saturated or unsaturated hydrocarbons include benzene, toluene,
cyclohexane, and xylenes.
A first aspect of the present invention provides a crystalline Form B of
{(li?,2,S*,31S*,4i?,51S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II.
Figure imgf000005_0001
Formula II
In one embodiment of this aspect, the crystalline Form B of {(\R,2S,3S,4R,5S)-5- [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl}methyl acetate of Formula II is characterized by an X-ray powder diffraction (XRPD) pattern having characteristic peak values at 5.6, 14.7, 16.8, 20.7, and 24.4 ±0.2° 2Θ.
In another embodiment of this aspect, the crystalline Form B of {(l i^^S^^ ?^^)- 5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl}methyl acetate of Formula II is further characterized by an XRPD pattern having characteristic peak values at 11.0, 12.0, 13.2, 13.9, 17.4, 18.9, 19.4, 22.5, 23.5, 28.0, and 29.4 ±0.2° 2Θ.
In another embodiment of this aspect, the crystalline Form B of {(l i^^S^^ ?^^)- 5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl}methyl acetate of Formula II is characterized by an XRPD pattern substantially as depicted in Figure 1, Figure 2, or Figure 3. Table 1 provides the 2Θ values, the corresponding d-spacing values (A), and the relative intensity of the crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl} methyl acetate of Formula II prepared as per Example 1.
Figure imgf000006_0001
*The relative peak intensities may vary depending on the crystal size and habit.
Table 2 provides the 2Θ values, the corresponding d-spacing values (A), and the relative intensity of the crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl} methyl acetate of Formula II prepared as per Example 2.
Figure imgf000007_0001
The relative peak intensities may vary depending on the crystal size and habit. Table 3 provides the 2Θ values, the corresponding d-spacing values (A), and the relative intensity of the crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl} methyl acetate of Formula II prepared as per Example 3.
Figure imgf000008_0001
*The relative peak intensities may vary depending on the crystal size and habit.
In one embodiment of this aspect, the crystalline Form B of {(ϋϊ^,Β^^Λ^^)^- [4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl} methyl acetate of Formula II is characterized by a differential scanning calorimetric (DSC) thermogram having an endothermic peak at about 171°C.
In another embodiment of this aspect, the crystalline Form B of {(l i^^S^^ ?^^)- 5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl}methyl acetate of Formula II is characterized by a DSC thermogram substantially as depicted in Figure 4, Figure 5, or Figure 6.
A second aspect of the present invention provides a process for the preparation of a crystalline Form B of {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II,
Figure imgf000009_0001
Formula II
comprising the steps of:
a) treating {(li?,2,S',31S',4i?,51S)-5-[4-chloro-3-(4-e1hoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II with a solvent; and
b) isolating the crystalline Form B of {(lR,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II.
In one embodiment of this aspect, the present invention provides a process for the preparation of the crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl} methyl acetate of Formula II comprising the steps of:
a) dissolving {(li?,2,S*,3^4i?,51S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate in an alcohol solvent;
b) stirring the reaction mixture of step a) to obtain a solid; and
c) isolating the crystalline Form B of {(lR,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate. {(li?,21S*,31S*,4i?,51S)-5-[4-Chloro-3-(4-e1hoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II used as the starting material can be prepared by methods known in the art, for example, PCT Publication No. WO
2014/159151.
Preferably, the alcohol solvent is selected from the group comprising primary, secondary, and tertiary alcohols having from one to six carbon atoms. More preferably, the alcohol solvent is selected from the group comprising methanol, ethanol, «-propanol, isopropanol, butanol, 2-methoxy ethanol, and 2-ethoxy ethanol.
Step a) includes dissolving {(1^2S,3S,4R,5S)-5-[4-cMoro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1-yl} methyl acetate of Formula II in an alcohol solvent at a temperature of about 25°C to about 80°C to obtain a clear solution.
Step b) includes cooling the solution to about 5°C to about 25 °C, and then stirring at a temperature of about 5°C to about 25°C for about 45 minutes to about 90 minutes to obtain a solid.
Step c) of isolating the crystalline Form B of {(lR,25,,35,,4R,55)-5-[4-chloro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1-yl} methyl acetate of Formula II includes employing one or more techniques selected from the group consisting of filtration, decantation, extraction, distillation, evaporation, chromatography, precipitation, concentration, crystallization, centrifugation, and recrystallization. The crystalline Form B of {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II may further be dried using conventional techniques, for example, drying, drying under reduced pressure, spray drying, freeze drying, air drying, or agitated thin film drying.
A third aspect of the present invention provides a pharmaceutical composition comprising a crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4-c loro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2. l]oct- 1-yl} methyl acetate of Formula II and one or more pharmaceutically acceptable carriers, diluents, or excipients.
A fourth aspect of the present invention provides the use of a crystalline Form B of {(li?,2,S*,31S*,4i?,51S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II for the treatment of type 2 diabetes mellitus. A fifth aspect of the present invention provides a process comprising converting a crystalline Form B of {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II to ertugliflozin.
In one embodiment of this aspect, the conversion of the crystalline Form B of {(li?,2,S*,31S*,4i?,51S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II to ertugliflozin may be carried out using deacetylating agents. Preferably, the deacetylating agent is sodium methoxide.
In one embodiment of this aspect, the conversion of the crystalline Form B of { ( \R,2S,3S,4R,5S)-5 -[4-chloro-3 -(4-ethoxybenzyl)phenyl] -2,3 ,4-trihydroxy-6, 8- dioxabicyclo[3.2. l]oct-l-yl} methyl acetate of Formula II to ertugliflozin may be carried by methods known in the art, for example, PCT Publication No. WO 2014/159151.
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:
XRPD patterns of the samples were recorded using a PANalytical® X'pert PRO with X'celerator® as the detector, 0.02 as step size, and 3-40° 2Θ as range, using CuKa radiation.
DSC thermograms of the samples were recorded using a Mettler Toledo® Stai*, SW 11.0, temperature range 30°C to 300°C, heating rate: 10°C/min., nitrogen flow: 20.0 mL/min.
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 a crystalline Form B of {(Ti?.2<S'.3iS'.4i?.5iS')-5-r4-chloro-3-(4- ethoxybenzyl)phenyll-2.3.4-trihydroxy-6.8-dioxabicvclor3.2. Hoct-l-yl} methyl acetate of Formula II
{(li?,21S*,3,S*,4i?,51S)-5-[4-Chloro-3-(4-e1hoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate (1 g) was added to ethanol (7 mL), and the mixture was heated to 65°C to 70°C to obtain a clear solution. The solution was cooled to 20°C, and then stirred at 20°C to 25°C for 60 minutes. The solid obtained was filtered, and then washed with ethanol (3 mL). The solid was dried under reduced pressure at 40°C to 45°C for 2 hours to obtain the title compound.
Yield: 0.214 g
Example 2: Preparation of a crystalline Form B of UlR.2S,3SAR.5S)-5-\4-c loro-3-(4- ethoxybenzvnphenyll-2.3.4-trihvdroxy-6.8-dioxabicvclor3.2. Hoct-l-yl} methyl acetate of Formula II
{(li?,21S*,3,S*,4i?,51S)-5-[4-Chloro-3-(4-e1hoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate (1 g) was added to methanol (7 mL), and the mixture was heated to 57°C to 60°C to obtain a clear solution. The solution was cooled to 21°C, and then stirred at 20°C to 25°C for 60 minutes. The solid obtained was filtered, and then washed with methanol (3 mL). The solid was dried under reduced pressure at 40°C to 45°C for 2 hours to obtain the title compound.
Yield: 0.224 g
Example 3: Preparation of a crystalline Form B of (lR.2S,3SAR.5S)-5-\4-c loro-3-(4- ethoxybenzyl)phenyll-2.3.4-trihydroxy-6.8-dioxabicvclor3.2. Hoct-l-yl} methyl acetate of Formula II
{(li?,21S*,3,S*,4i?,51S)-5-[4-Chloro-3-(4-e1hoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate (1.2 g) was added to isopropyl alcohol (24 mL), and the mixture was heated to 75°C to obtain a clear solution. The solution was cooled to 5°C, and then stirred at 5°C to 10°C for 60 minutes. The solid obtained was filtered, and then washed with isopropyl alcohol (3 mL). The solid was dried under reduced pressure at 40°C to 45°C for 2 hours to obtain the title compound.
Yield: 0.38 g

Claims

We claim:
A crystalline Form B of {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]- 2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II characterized by an X-ray powder diffraction (XRPD) pattern having characteristic peak values at 5.6, 14.7, 16.8, 20.7, and 24.4 ±0.2° 2Θ.
Figure imgf000013_0001
Formula II
2. The crystalline Form B of {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]- 2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II according to claim 1, further characterized by an XRPD pattern having characteristic peak values at 11.0, 12.0, 13.2, 13.9, 17.4, 18.9, 19.4, 22.5, 23.5, 28.0, and 29.4 ±0.2° 2Θ.
3. A crystalline Form B of {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]- 2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II characterized by an XRPD pattern substantially as depicted in Figure 1, or Figure 2, or Figure 3.
4. A crystalline Form B of {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]- 2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II characterized by a differential scanning calorimetric (DSC) thermogram having an endothermic peak at about 171 °C .
5. A crystalline Form B of {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]- 2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II characterized by a DSC thermogram substantially as depicted in Figure 4, or Figure 5, or Figure 6.
6. A process for the preparation of a crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4- chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl} methyl acetate of Formula II,
Figure imgf000014_0001
Formula II
comprising the steps of:
a) treating {(li?,25',35',4i?,55)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II with a solvent; and
b) isolating the crystalline Form B of {(li?,2S,3S,4i?,5¾-5-[4-chloro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II.
7. The process according to claim 6, wherein the solvent is selected from the group
consisting of water, esters, alkanols, halogenated hydrocarbons, ketones, ethers, polar aprotic solvents, saturated or unsaturated hydrocarbons, and mixtures thereof.
8. A process for the preparation of a crystalline Form B of {(\R,2S,3S,4R,5S)-5-[4- chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l- yl}methyl acetate of Formula II comprising the steps of:
a) dissolving {(li?,21S*,3^,4i?,5,S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4- trihydroxy-6,8-dioxabicyclo[3.2. l]oct-l-yl} methyl acetate in an alcohol solvent;
b) stirring the reaction mixture of step a) to obtain a solid; and
c) isolating the crystalline Form B of {(li?,2S,3S,4i?,5¾-5-[4-chloro-3-(4- ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-l-yl}methyl acetate.
9. The process according to claim 8, wherein the alcohol solvent is selected from the group consisting of primary, secondary, and tertiary alcohols having from one to six carbon atoms.
10. The process according to claim 8 or 9, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, «-propanol, isopropanol, butanol, 2- methoxyethanol, and 2-ethoxyethanol.
1 1. A process for the preparation of ertugliflozin comprising converting a crystalline Form B of {(li?,2,S*,31S*,4i?,51S)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II to ertugliflozin.
12. The process according to claim 1 1, wherein the conversion of the crystalline Form B of {( li?,2,S*,31S*,4i?,51S)-5-[4-chloro-3-(4-e1hoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8- dioxabicyclo[3.2.1]oct-l-yl}methyl acetate of Formula II to ertugliflozin is carried out using deacetylating agents.
13. The process according to claim 12, wherein the deacetylating agent is sodium
methoxide.
PCT/IB2017/050581 2016-02-05 2017-02-03 Crystalline form of {(1r,2s,3s,4r,5s)-5-[4-chloro-3-(4-ethoxybenzyl)phenyl]-2,3,4-trihydroxy-6,8-dioxabicyclo[3.2.1]oct-1-yl}methyl acetate WO2017134606A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107857768A (en) * 2018-01-04 2018-03-30 威海贯标信息科技有限公司 A kind of net novel crystal forms of Ai Gelie
WO2020026273A1 (en) * 2018-07-31 2020-02-06 Msn Laboratories Private Limited, R&D Center Solid forms of ertugliflozin free base and solid dispersions comprising ertugliflozin l-pyroglutamic acid.

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WO2014159151A1 (en) * 2013-03-14 2014-10-02 Msd International Gmbh Methods for preparing sglt2 inhibitors

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WO2014159151A1 (en) * 2013-03-14 2014-10-02 Msd International Gmbh Methods for preparing sglt2 inhibitors

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BOWLES ET AL.: "Commercial Route Research and Development for SGLT2 Inhibitor Candidate Ertugliflozin", ORGANIC PROCESS SEARCH & DEVELOPMENT, vol. 18, 2014, pages 66 - 81, XP055283061, Retrieved from the Internet <URL:http://pubs.acs.org/doi/abs/10.1021/op4002802> [retrieved on 20170312] *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107857768A (en) * 2018-01-04 2018-03-30 威海贯标信息科技有限公司 A kind of net novel crystal forms of Ai Gelie
WO2020026273A1 (en) * 2018-07-31 2020-02-06 Msn Laboratories Private Limited, R&D Center Solid forms of ertugliflozin free base and solid dispersions comprising ertugliflozin l-pyroglutamic acid.

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