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WO2010068605A1 - Novel polymorphic forms of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1h-pyrazole-3-yl]4-deoxy-4-fluoro-beta-d-glucopyranoside including hydrates thereof and the preparations thereof - Google Patents

Novel polymorphic forms of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1h-pyrazole-3-yl]4-deoxy-4-fluoro-beta-d-glucopyranoside including hydrates thereof and the preparations thereof Download PDF

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Publication number
WO2010068605A1
WO2010068605A1 PCT/US2009/067053 US2009067053W WO2010068605A1 WO 2010068605 A1 WO2010068605 A1 WO 2010068605A1 US 2009067053 W US2009067053 W US 2009067053W WO 2010068605 A1 WO2010068605 A1 WO 2010068605A1
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WO
WIPO (PCT)
Prior art keywords
pyrazole
deoxy
fluoro
glucopyranoside
methoxyphenyl
Prior art date
Application number
PCT/US2009/067053
Other languages
French (fr)
Inventor
Bruno Baumgartner
Harald Berchtold
Stephen Byard
Timothy Donegan
Harpal S. Gill
Harvey Lieberman
Norbert Nagel
Oliver Plettenburg
Elizabeth Secord
Franz J. Weiberth
Yong Yu
Boris Gordonov
Original Assignee
Sanofi-Aventis
Gordonov, Natalia
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Publication of WO2010068605A1 publication Critical patent/WO2010068605A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
    • 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

Definitions

  • the present invention relates to the preparation of novel polymorphic forms of 4-[(4- methoxyphenylJmethyll- ⁇ - ⁇ hfluoromethylJ-I H-pyrazole-S-yll ⁇ -deoxy ⁇ -fluoro-beta-D- glucopyranoside and hydrates thereof which are suitable for the treatment of certain diseases and conditions including, but not limited to, diabetes.
  • a primary concern for the manufacture of large-scale pharmaceutical compounds is that the active substance should have a stable crystalline form to ensure consistent processing parameters and pharmaceutical quality. If an unstable crystalline form is used, that crystalline form may change during manufacture and/or storage resulting in quality control problems, and formulation irregularities. Such a change may affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality and stringent requirements imposed on formulations of pharmaceutical compositions.
  • the large-scale manufacturing of a pharmaceutical composition poses many challenges to the chemist and chemical engineer. While many of these challenges relate to the handling of large quantities of reagents and control of large-scale reactions, the handling of the final product poses special challenges linked to the nature of the final active product itself. Not only must the product be prepared in high yield, stable, substantially free of impurities and capable of ready isolation, the product must possess properties that are suitable for the types of pharmaceutical preparations in which they are likely to be ultimately used. The stability of the active ingredient of the pharmaceutical preparation must be considered during each step of the manufacturing process, including the synthesis, isolation, bulk storage, pharmaceutical formulation and long-term formulation. Each of these steps may be impacted by various environmental conditions of temperature and humidity.
  • the pharmaceutically active substance used to prepare the pharmaceutical compositions should be as pure as possible and its chemical and physico-chemical stability on long-term storage must be assured under various environmental conditions. This is needed to prevent the appearance of unintended degradation products in pharmaceutical compositions. As such degradation products may be potentially toxic or result simply in reducing the potency of the composition.
  • the present invention comprises novel polymorphic forms of a drug substance, 4-[(4- methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D- glucopyranoside, and hydrates thereof.
  • a drug substance 4-[(4- methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D- glucopyranoside
  • hydrates thereof Although widespread, not all pharmaceutically active compounds form hydrates or solvates. The existence of hydrates, their crystal structure and properties are unpredictable and therefore not obvious.
  • the present invention comprises process for the preparation of novel polymorphic 4- [(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside, and hydrates thereof substantially free of residual organic solvent contaminants and impurities.
  • Said compound can exist in at least 4 crystalline forms of varying degrees of hydration.
  • the present invention also comprises administering to a patient in need of treatment a therapeutically effective amount of a composition comprising at least one crystalline form selected from the group consisting of Form B, Form C and Form D.
  • Form B of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D- glucopyranoside dihydrate ( Figure I wherein n is 2) is characterized by the following peaks as measured by XPRD: 5.20, 6.57, 9.01 , 10.41 , 11.39, 13.19, 15.43, 15.85, 17.95, 18.79, 19.91 , 20.32, 20.72, 21.26, 21.90, 22.39, 23.37, 23.87, 24.41 , 24.73, 25.08, 26.48, 28.52 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation.
  • Form B is characterized by representative peaks at 5.2, 6.57, 13.19, 19.91 , 21.26 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. Further Form B is characterized by infrared: peaks found at 1513, 1504 and 1160 +/-1 cm "1 .
  • Form C of 4-[(4-methoxyphenyl)nnethyl]-5-(trifluoronnethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside ( Figure I wherein n is 0) is characterized by the following peaks as measured by XPRD: 4.30, 8.61 , 11.21 , 15.88, 17.29, 18.63, 19.61 , 20.45, 20.48, 21.14, 21.47, 22.65, 23.39, 25.43, 27.01 , 28.52, 30.34 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation.
  • Form C is characterized by representative peaks at 4.3, 8.61 , 15.88, 20.45, 22.65 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. Further Form C is characterized by infrared: peaks found at 1508 (with a shoulder) and 1023 +/-1 cm "1 .
  • Form D is characterized by representative peaks at 7.57, 14.55, 19.97, 20.61 , 22.77 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. Further Form D is characterized by infrared: peaks found at 1512, 1481 , 1460 and 1440 +/-1 cm "1 .
  • Figure 1 is the structure of 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside and hydrates thereof.
  • Figure 2 is the XPRD of Form B the dihydrate of 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside
  • Figure 3 is the Infrared Spectrum of Form B
  • Figure 4 is the Differential Scanning Calohmetry Trace of Form B
  • Figure 5 is the TGA of Form B
  • Figure 6 is the XPRD of Form C
  • Figure 7 is the Infrared Spectrum of Form C
  • Figure 8 is the Raman Spectrum of Form C
  • Figure 9 is the Differential Scanning Calohmetry Trace of Form C
  • Figure 10 is the TGA of Form C
  • Figure 11 is the XPRD of Form D
  • Figure 12 is the Infrared Spectrum of Form D
  • Figure 13 is the Raman Spectrum of Form D
  • Figure 14 is the Differential Scanning Calorimetry Trace of Form D
  • FIG. 15 is the TGA of Form D Detailed Description of the Invention
  • the present invention relates to novel physical forms of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4- fluoro-beta-D-glucopyranoside, each with its own unique physico-chemical properties.
  • Form D is a monohydrate.
  • Form C is an anhydrate and Form B is a dihydrate.
  • Form B may be produced from essentially pure 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate in a heterogeneous manner.
  • Temperature ramping rates, aging, temperature/times, the presence of additives and pH are important in controlling the form of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside that is isolated.
  • Additives other than KOAc/HOAc such as, for example, NaOAc, LiOAc, KCI, NaCI, LiCI, K 3 PO 4 , HK 2 PO 4 , H 2 KPO 4 , and their respective Na, Li, Mg, and Zn salts may also be used in the crystallization/recrystallization processes.
  • Form B may be isolated from crystallization of essentially pure 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside using 1 -PrOH/HOAc/water or 1 -PrOH/THF/water.
  • Form B may also be isolated from isopropyl acetate/n-heptane solutions when the water content is between 3 and 10 equivalents after formation of a monohydrate. Under these conditions, but with water content greater than 10 equivalents, Form B may be obtained directly.
  • Form B may be obtained by stirring suspensions of 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate at 20 0 C in alcohol/water mixtures with a water activity of 0.7 or higher.
  • Form C is obtained by dissolving essentially pure 4-[(4-methoxyphenyl)methyl]- 5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate in isopropyl acetate. The aforesaid solution is then heated to drive off water at high temperature prior to precipitation by addition of n-heptane. Form C may also be obtained from the melt of a hydrate.
  • Form D may be prepared by stirring suspensions of a hydrate or an anhydrate in alcohol/water systems at high temperature, such as, for example, above 60 0 C.
  • Form D may also be isolated by crystallization from a solution of essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside in aqueous ethanol or in aqueous isopropanol and isolating at high temperature, such as, for example, above 60°C
  • thermogravimetric analyses are performed with a METTLER TGA85 1 e (module TGAISDTA85 1 elSF 1 1001042). Open 100p1 A1203 crucibles are used and the measurements are performed in a nitrogen gas flow of 50 mL/min. The measured data is evaluated via the software STARe V8.10.
  • Infra-red absorption spectra are recorded on a FT-IR Spectrometer (Nexus 470, NICOLET). The spectra are evaluated and plotted by the software Omnic V. 6.1 A.
  • crystallization experiments may be performed with essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside (for example, greater than 98% HPLC purity).
  • a 40 ml_ vial was charged with 15ml_ of a basic aqueous solution (6.36 wt% of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside).
  • a sodium salt of the pyrazole functionality, or other suitable salt of the pyrazole could be used to prepare the solution, lsopropyl acetate (15 ml_) and glacial acetic acid (0.28ml_) were added. The resultant biphasic mixture was stirred vigorously for 60 minutes.
  • Figure 1 is the structure of 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside and hydrates thereof.
  • Figure 2 is the XPRD of Form B the dihydrate of 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside
  • Figure 3 is the Infrared Spectrum of Form B
  • Figure 4 is the Differential Scanning Calohmetry Trace Thermogram of Form B
  • Figure 5 is the TGA of Form B
  • Figure 6 is the XPRD of Form C
  • Figure 7 is the Infrared Spectrum of Form C
  • Figure 8 is the Raman Spectrum of Form C
  • Figure 9 is the Differential Scanning Calohmetry Trace of Form C
  • Figure 10 is the TGA of Form C
  • Figure 11 is the XPRD of Form D
  • Figure 12 is the Infrared Spectrum of Form D
  • Figure 13 is the Raman Spectrum of Form D
  • Figure 14 is the Differential Scanning Calorimetry Trace of Form D
  • Figure 15 is the TGA of Form D

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Abstract

The present invention is directed to stable polymorphic forms of the compound of formula Il and hydrates thereof: i. e., a solvent free polymorph "C" of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)- 1H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside; a monohydrate form "D"; and a dihydrate form "B", each substantially free of residual organic solvent contaminants and impurities.

Description

Novel Polymorphic Forms of 4-r(4-Methoxyphenyl)methyll-5-(trifluoromethyl)- 1 H-pyrazole-3-vn-4-deoxy-4-fluoro-foefa-D-qlucopyranoside Including Hydrates
Thereof and the Preparations Thereof
Field of the Invention
The present invention relates to the preparation of novel polymorphic forms of 4-[(4- methoxyphenylJmethyll-δ-^hfluoromethylJ-I H-pyrazole-S-yll^-deoxy^-fluoro-beta-D- glucopyranoside and hydrates thereof which are suitable for the treatment of certain diseases and conditions including, but not limited to, diabetes.
Background of the Invention
Published United States Patent Application US 2004 /0259819 discloses certain heterocyclic fluoroglycoside derivatives having an effect on SGLTs. More particularly, said published application discloses the use of 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-i H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside (figure 1 , n = 0) for treating diabetes by affecting SGLT2.
Figure imgf000003_0001
Figure 1
The preparation of 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]- 4-deoxy-4-fluoro-beta-D-glucopyranoside is disclosed in Published United States Patent Application US 2004 /0259819. However, the aforementioned patent application makes no mention as to the polymorphic form, hydration state or physical purity of the compound provided from the procedure. Furthermore, there is no reported physical chemical data reported for 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-i H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside in said published application that suggests the physical form of the product obtained.
A primary concern for the manufacture of large-scale pharmaceutical compounds is that the active substance should have a stable crystalline form to ensure consistent processing parameters and pharmaceutical quality. If an unstable crystalline form is used, that crystalline form may change during manufacture and/or storage resulting in quality control problems, and formulation irregularities. Such a change may affect the reproducibility of the manufacturing process and thus lead to final formulations which do not meet the high quality and stringent requirements imposed on formulations of pharmaceutical compositions.
The large-scale manufacturing of a pharmaceutical composition poses many challenges to the chemist and chemical engineer. While many of these challenges relate to the handling of large quantities of reagents and control of large-scale reactions, the handling of the final product poses special challenges linked to the nature of the final active product itself. Not only must the product be prepared in high yield, stable, substantially free of impurities and capable of ready isolation, the product must possess properties that are suitable for the types of pharmaceutical preparations in which they are likely to be ultimately used. The stability of the active ingredient of the pharmaceutical preparation must be considered during each step of the manufacturing process, including the synthesis, isolation, bulk storage, pharmaceutical formulation and long-term formulation. Each of these steps may be impacted by various environmental conditions of temperature and humidity.
The pharmaceutically active substance used to prepare the pharmaceutical compositions should be as pure as possible and its chemical and physico-chemical stability on long-term storage must be assured under various environmental conditions. This is needed to prevent the appearance of unintended degradation products in pharmaceutical compositions. As such degradation products may be potentially toxic or result simply in reducing the potency of the composition.
The present invention comprises novel polymorphic forms of a drug substance, 4-[(4- methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D- glucopyranoside, and hydrates thereof. Although widespread, not all pharmaceutically active compounds form hydrates or solvates. The existence of hydrates, their crystal structure and properties are unpredictable and therefore not obvious.
Summary of the Invention
The present invention comprises process for the preparation of novel polymorphic 4- [(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside, and hydrates thereof substantially free of residual organic solvent contaminants and impurities. Said compound can exist in at least 4 crystalline forms of varying degrees of hydration.
The present invention also comprises administering to a patient in need of treatment a therapeutically effective amount of a composition comprising at least one crystalline form selected from the group consisting of Form B, Form C and Form D.
Form B of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D- glucopyranoside dihydrate (Figure I wherein n is 2) is characterized by the following peaks as measured by XPRD: 5.20, 6.57, 9.01 , 10.41 , 11.39, 13.19, 15.43, 15.85, 17.95, 18.79, 19.91 , 20.32, 20.72, 21.26, 21.90, 22.39, 23.37, 23.87, 24.41 , 24.73, 25.08, 26.48, 28.52 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. In particular Form B is characterized by representative peaks at 5.2, 6.57, 13.19, 19.91 , 21.26 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. Further Form B is characterized by infrared: peaks found at 1513, 1504 and 1160 +/-1 cm"1. Form C of 4-[(4-methoxyphenyl)nnethyl]-5-(trifluoronnethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside (Figure I wherein n is 0) is characterized by the following peaks as measured by XPRD: 4.30, 8.61 , 11.21 , 15.88, 17.29, 18.63, 19.61 , 20.45, 20.48, 21.14, 21.47, 22.65, 23.39, 25.43, 27.01 , 28.52, 30.34 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. In particular Form C is characterized by representative peaks at 4.3, 8.61 , 15.88, 20.45, 22.65 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. Further Form C is characterized by infrared: peaks found at 1508 (with a shoulder) and 1023 +/-1 cm"1.
Form D of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside monohydrate (Figure I wherein n is 1 ) is characterized by the following peaks as measured by XPRD: 5.97, 7.57, 12.22, 14.55, 15.20, 18.39, 19.51 , 19.97, 20.51 , 22.52, 22.77, 24.08, 26.56, 27.37, 28.12 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. In particular Form D is characterized by representative peaks at 7.57, 14.55, 19.97, 20.61 , 22.77 +/- 0.2 degrees 2-theta as measured using copper K-alpha radiation. Further Form D is characterized by infrared: peaks found at 1512, 1481 , 1460 and 1440 +/-1 cm"1.
Detailed Description of the Drawings
Figure 1 is the structure of 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside and hydrates thereof.
Figure 2 is the XPRD of Form B the dihydrate of 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside
Figure 3 is the Infrared Spectrum of Form B
Figure 4 is the Differential Scanning Calohmetry Trace of Form B
Figure 5 is the TGA of Form B
Figure 6 is the XPRD of Form C Figure 7 is the Infrared Spectrum of Form C
Figure 8 is the Raman Spectrum of Form C
Figure 9 is the Differential Scanning Calohmetry Trace of Form C
Figure 10 is the TGA of Form C Figure 11 is the XPRD of Form D
Figure 12 is the Infrared Spectrum of Form D
Figure 13 is the Raman Spectrum of Form D
Figure 14 is the Differential Scanning Calorimetry Trace of Form D
Figure 15 is the TGA of Form D Detailed Description of the Invention
The preparation of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside is disclosed in Published United States Patent Application US 2004 /0259819. However, the aforementioned patent application makes no mention as to the physical form or state of hydration of the compound provided from the procedure. Neither is any physical chemical data reported for 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside in Application US 2004 /0259819 that would suggest the particular physical form of the product obtained. The present invention relates to novel physical forms of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4- fluoro-beta-D-glucopyranoside, each with its own unique physico-chemical properties. Form D is a monohydrate. Form C is an anhydrate and Form B is a dihydrate.
The procedures described herein provide novel and unexpected stable polymorphs and hydrates of this compound or a tautomer thereof. These experiments comprise thermodynamically controlled crystallizations of essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside hydrated forms by varying solvent and cooling rate and also by adding anti-solvents. The particular forms may also be produced through maturation procedures and/or dehydration of hydrates.
Form B may be produced from essentially pure 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate in a heterogeneous manner. For example, crystallization/recrystallization of essentially pure 4-[(4-methoxyphenyl)methyl]- 5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside from n-propanol/water mixture containing 1 .9 equivalents of KOAc/HOAc (pH about 6) at onset of 22 - 32°C initially produces a monohydrate. However, heating and digesting the above mixture at about 35°C, then slow cooling and aging at about 1 °C, gives Form B on isolation by filtration under vacuum. Temperature ramping rates, aging, temperature/times, the presence of additives and pH are important in controlling the form of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside that is isolated. Additives other than KOAc/HOAc, such as, for example, NaOAc, LiOAc, KCI, NaCI, LiCI, K3PO4, HK2PO4, H2KPO4, and their respective Na, Li, Mg, and Zn salts may also be used in the crystallization/recrystallization processes.
Form B may be isolated from crystallization of essentially pure 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside using 1 -PrOH/HOAc/water or 1 -PrOH/THF/water. Form B may also be isolated from isopropyl acetate/n-heptane solutions when the water content is between 3 and 10 equivalents after formation of a monohydrate. Under these conditions, but with water content greater than 10 equivalents, Form B may be obtained directly. Furthermore, Form B may be obtained by stirring suspensions of 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate at 200C in alcohol/water mixtures with a water activity of 0.7 or higher.
Form C is obtained by dissolving essentially pure 4-[(4-methoxyphenyl)methyl]- 5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate in isopropyl acetate. The aforesaid solution is then heated to drive off water at high temperature prior to precipitation by addition of n-heptane. Form C may also be obtained from the melt of a hydrate.
Form D may be prepared by stirring suspensions of a hydrate or an anhydrate in alcohol/water systems at high temperature, such as, for example, above 600C. Form D may also be isolated by crystallization from a solution of essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside in aqueous ethanol or in aqueous isopropanol and isolating at high temperature, such as, for example, above 60°C
All X-ray powder diffraction experiments (XPRD) are performed with a STOE Stadi-P transmission diffractometer using Cu-Kαi radiation. For room temperature powder diffraction, linear position sensitive detectors are used. Dry samples are investigated in a flat preparation. The measured data is evaluated and plotted with the software WinXPOW v2.12.
All DSC measurements are performed with a METTLER DSC822e (module DSC822e/700/109/414935/0025). If not indicated differently, 4OpL Al-crucibles with sealed lid and hole are used. All measurements are carried out in a nitrogen gas flow of 50 mL/min and typical heating rates range from 1 to 50o/min. The measured data is evaluated via the software provided with said instrument.
The thermogravimetric analyses are performed with a METTLER TGA85 1 e (module TGAISDTA85 1 elSF 1 1001042). Open 100p1 A1203 crucibles are used and the measurements are performed in a nitrogen gas flow of 50 mL/min. The measured data is evaluated via the software STARe V8.10.
Infra-red absorption spectra are recorded on a FT-IR Spectrometer (Nexus 470, NICOLET). The spectra are evaluated and plotted by the software Omnic V. 6.1 A.
Raman spectra are recorded with an FT-Raman spectrometer (RFS-1 OOIS, BRUKER) equipped with a 1 .5 W NIR-Laser (Nd:YAG; h=1064 nm) and a nitrogen-cooled D4 1 8-T NIR-Detector. The spectra are evaluated and plotted by the software OPUS V. 4.2.
If not stated differently, the crystallization experiments may be performed with essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside (for example, greater than 98% HPLC purity).
The following examples detailed below are provided to more specifically describe and to better teach how to make and practice the claimed compounds of the present invention and methods for their preparation. The examples are provided for illustrative purposes only and it is to be recognized that not all embodiments of the invention can be disclosed in this manner. Therefore, the examples are to be construed in this way and should not be interpreted as limiting the spirit and scope of the invention. Example 1a Preparation of Form B
Essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4- deoxy-4-fluoro-beta-D-glucopyranoside monohydrate (0.218 g) was allowed to maturate in 1.5 ml_ of water/ethanol (vol/vol 1 :1 ) at 200C for up to six weeks. The solids in the slurry were identified as Form B.
Example 1b Preparation of Form B
Essentially pure 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H-pyrazole-3-yl]-4- deoxy-4-fluoro-beta-D-glucopyranoside monohydrate (5g) was allowed to maturate overnight in 125 ml_ of a 1 -propanol (25%)/water (75%) mixture at room temperature (200C). After filtration, solids were identified as Form B.
Example 1c Preparation of Form B
Essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside (5Og) was added to a reactor along with 150 ml_ of 1 -PrOH, 150 ml_ water, 20.6g of KOAc and 6.3ml_ of HOAc. The resultant mixture was stirred to dissolve and filtered into a 3L jacketed reactor. The filter was washed with 10OmL of 1 -PrOH/water (1 :1 ) and the washes added to the reactor. The solution was warmed to 45°C with stirring at which point an additional 55OmL of water were added over 4 minutes. The solution was reheated to 45°C and then cooled to 29°C over 23 minutes followed by cooling to 22°C at 4.5°C/hour. The thick suspension obtained was heated to 36°C, held for 80 minutes and then cooled at 3°C/hour to 10C and left to age overnight. A sample removed at this point was confirmed to be dihydrate Form B. The slurry was filtered, washed with water and dried yielding Form B. Example 1d Preparation of Form B
A 40 ml_ vial was charged with 15ml_ of a basic aqueous solution (6.36 wt% of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside). A sodium salt of the pyrazole functionality, or other suitable salt of the pyrazole could be used to prepare the solution, lsopropyl acetate (15 ml_) and glacial acetic acid (0.28ml_) were added. The resultant biphasic mixture was stirred vigorously for 60 minutes. After phase separation the organic phase was charged into a clean 4OmL vial and the water content was determined to be 25 equivalents by KF titration. A 9ml_ aliquot of this solution was removed, heated to 67°C and held at this temperature for 1 hour. n-Heptane (13.5 ml_) was added in two portions (9ml_ and 4.5ml_) and the solution was cooled to 25°C. A sample was taken and the contents were identified as Form B. After continuing to stir overnight at 25°C, the sample remained Form B.
Example 2a Preparation of Form C
Keeping a melt of a hydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside at 130 C for 6 hours provides Form C.
Example 2b Preparation of Form C
4-[(4-Methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4- fluoro-beta-D-glucopyranoside (2Og) was dissolved in 250 ml_ of isopropyl acetate at 300C. The resultant solution was concentrated to remove water and additional isopropyl acetate was added so that the volume reached 133 ml_. This solution was heated to 72°C, 133 ml_ of n-heptane were added and the mixture was held at 72°C until precipitation occurred. The slurry was cooled to room temperature, solids isolated by vacuum filtration and dried in a vacuum oven at 500C, yielding form C.
Example 3a Preparation of Form D
4-[(4-Methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4- fluoro-beta-D-glucopyranoside (0.51 g) was added to a 30 mL jacketed tube followed by 5 mL of 16.7% 1 -PrOH in water. The slurry was stirred and heated to 65°C to ensure dissolution. Water (5ml_) was added to precipitate out solids (temperature of slurry was 59.7°C). The slurry was filtered hot yielding Form D.
Referring now to the drawings,
Figure 1 is the structure of 4-[(4-methoxyphenyl)methyl]-5-(thfluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside and hydrates thereof.
Figure 2 is the XPRD of Form B the dihydrate of 4-[(4-methoxyphenyl)methyl]-5- (thfluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside
Figure 3 is the Infrared Spectrum of Form B
Figure 4 is the Differential Scanning Calohmetry Trace Thermogram of Form B
Figure 5 is the TGA of Form B
Figure 6 is the XPRD of Form C
Figure 7 is the Infrared Spectrum of Form C
Figure 8 is the Raman Spectrum of Form C
Figure 9 is the Differential Scanning Calohmetry Trace of Form C Figure 10 is the TGA of Form C
Figure 11 is the XPRD of Form D
Figure 12 is the Infrared Spectrum of Form D
Figure 13 is the Raman Spectrum of Form D Figure 14 is the Differential Scanning Calorimetry Trace of Form D Figure 15 is the TGA of Form D

Claims

We claim:
1. The compound of formula I comprising a crystalline dihydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside of crystalline form B.
2. The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 13.19 as measured by XPRD using Copper K-alpha radiation.
3. The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 19.91 as measured by XPRD using Copper K-alpha radiation.
4. The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 20.72 as measured by XPRD using Copper K-alpha radiation.
5. The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 5.20 as measured by XPRD using Copper K-alpha radiation.
6. The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 26.48 as measured by XPRD using Copper K-alpha radiation.
7. The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 13.19 and 19.91 as measured by XPRD using Copper K-alpha radiation.
8. The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 13.19 and 19.91 and 21 .26 as measured by XPRD using Copper K-alpha radiation.
9. The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak selected from the group consisting of any two of the following of 13.19, 19.91 and 21 .26 as measured by XPRD using Copper K-alpha radiation.
10. The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak selected from the group consisting of any three of the following of 13.91 , 19.91 , 21 .26 and 20.72 as measured by XPRD using Copper K-alpha radiation.
1 1 . The compound of formula I as recited in claim 1 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside exhibiting two strong and slightly overlapping endothermic signals in the temperature range from about 30 0C to 1 10 0C in the DSC Thermogram curve.
12. The compound of formula I as recited in any one of claims 2 to 10 comprising crystalline form B of the dihydrate of 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside exhibiting two strong and slightly overlapping endothermic signals in the temperature range from about 30 0C to 1 10 0C in the DSC Thermogram curve.
13. A method of preparation the crystalline form B of the dihydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside by the recrystalization of essentially pure 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside using 1 -PrOH/HOAc/water.
14. A method of preparation the crystalline form B of the dihydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside by allowing essentially pure 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta- D-glucopyranoside to mature in a water/ethanol mixture at about 200C for six weeks.
15. The compound of formula I comprising a crystalline 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside of crystalline form C.
16. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside with a peak at 4.30 as measured by XPRD using Copper K-alpha radiation.
17. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside with a peak at 20.45 as measured by XPRD using Copper K-alpha radiation.
18. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside with a peak at 22.65 as measured by XPRD using Copper K-alpha radiation.
19. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside with a peak at 20.68 as measured by XPRD using Copper K-alpha radiation.
20. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside with a peak at 18.63 as measured by XPRD using Copper K-alpha radiation.
21. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside with a peak at 4.30 and 20.45 as measured by XPRD using Copper K-alpha radiation.
22. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside with a peak at 4.30 and 20.45 and 22.65 as measured by XPRD using Copper K-alpha radiation.
23. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside with a peak selected from the group consisting of any two of the following of 4.30, 20.45 and 22.65 as measured by XPRD using Copper K-alpha radiation.
24. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside with a peak selected from the group consisting of any three of the following of 4.30, 20.45, 22.65 and 20.68 as measured by XPRD using Copper K-alpha radiation.
25. The compound of formula I as recited in claim 15 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy- 4-fluoro-beta-D-glucopyranoside exhibiting a strong endothermic signal from about 150 0C to 155 0C in the DSC Thermogram curve.
26. The compound of formula I as recited in any one of claims 16 to 24 comprising crystalline form C of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside exhibiting a strong endothermic signal from about 150 0C to 155 0C in the DSC Thermogram curve.
27. A method of preparing the crystalline form C of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside comprising the steps of: 1 ) dissolving 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside or a hydrate thereof in isopropyl acetate;
2) concentrating to drive off the water; and
3) heating the resultant solution and adding an antisolvent to precipitate form C.
28. The compound of formula I comprising a crystalline monohydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside of crystalline form D.
29. The compound of formula I as recited in claim 28 comprising crystalline form D of a monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 19.97 as measured by XPRD using Copper K-alpha radiation.
30. The compound of formula I as recited in claim 28 comprising crystalline form d of a monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 5.97 as measured by XPRD using Copper K-alpha radiation.
31. The compound of formula I as recited in claim 28 comprising crystalline form D of a monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 22.77 as measured by XPRD using Copper K-alpha radiation.
32. The compound of formula I as recited in claim 28 comprising crystalline form D of monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 14.55 as measured by XPRD using Copper K-alpha radiation.
33. The compound of formula I as recited in claim 28 comprising crystalline form D of monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 20.51 as measured by XPRD using Copper K-alpha radiation.
34. The compound of formula I as recited in claim 28 comprising crystalline form D of monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 19.97 and 5.97 as measured by XPRD using Copper K-alpha radiation.
35. The compound of formula I as recited in claim 28 comprising crystalline form D of monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak at 19.97 and 5.97, and 22.77 as measured by XPRD using Copper K-alpha radiation.
36. The compound of formula I as recited in claim 28 comprising crystalline form D of a monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak selected from the group consisting of any two of the following of 19.97, 5.97 and 22.77 as measured by XPRD using Copper K-alpha radiation.
37. The compound of formula I as recited in claim 28 comprising crystalline form D of a monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside with a peak selected from the group consisting of any three of the following of 19.97, 5.97, 22.77 and 14.55 as measured by XPRD using Copper K-alpha radiation.
38. The compound of formula I as recited in claim 28 comprising crystalline form D of a monohydrate of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside exhibiting a strong endothermic signal from about 87 0C to 103 0C in the DSC Thermogram curve.
39. The compound of formula I as recited in any one of claims 29 to 37 comprising crystalline form D of a monohydrate of 4-[(4-methoxyphenyl)methyl]-5-
(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside exhibiting a strong endothermic signal from about 87 0C to 103 0C in the DSC Thermogram curve.
40. A method of preparation the crystalline form D of a monohydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside by the recrystallization of essentially pure 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta- D-glucopyranoside from aqueous ethanol.
41 . A method of preparation the crystalline form D of a monohydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside by the recrystallization of essentially pure 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta- D-glucopyranoside from aqueous isopropanol.
42. The method for the treatment of a diabetic patient in need thereof consisting of the administration of an efficacious amount of the compound of Claim 1.
43. The method for the treatment of a diabetic patient in need thereof consisting of the administration of an efficacious amount of the compound of Claim 15.
44. The method for the treatment of a diabetic patient in need thereof consisting of the administration of an efficacious amount of the compound of Claim 28.
45. A process for preparing crystalline Form B of the dihydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside comprising the steps of:
1 ) forming a monohydrate in an n-propanol/water mixture containing about 1 .9 equivalents of KOAc/HOAc wherein the pH is about 6;
2) heating and stirring the mixture at about 35°C; and
3) slowly cooling and stirring at about 1 °C.
46. A process for preparing crystalline Form B of the dihydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside comprising the step of crystallizing essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)- 1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside from 1 - PrOH/HOAc/water.
47. A process for preparing crystalline Form B of the dihydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside comprising the step of crystallizing essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)- 1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside from 1 - PrOH/THF/water.
48. A process for preparing crystalline Form B of the dihydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside comprising the step of crystallizing the dihydrate from a solution of the monohydrate in isopropyl acetate containing 3 to 10 equivalents of water and adding an antisolvent.
49. A process for preparing crystalline Form B of the dihydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside comprising the step of crystallizing essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)- 1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside from isopropyl acetate and n-heptane when the water content is greater than 10 equivalents.
50. A process for preparing crystalline Form B of the dihydrate of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside comprising the step of: slurrying a suspension of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H- pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside monohydrate at 200C in a mixture of alcohol/water with a water activity of 0.7 or higher.
51. A method of preparing the crystalline form C of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside comprising the steps of:
1 ) dissolving 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside or a hydrate thereof in isopropyl acetate;
2) concentrating to drive off the water; 3) heating the resultant solution; and
4) adding an antisolvent to precipitate form C.
52. A process for preparing crystalline Form C of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside comprising the steps of:
1 ) dissolving 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3- yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside or a hydrate in isopropyl acetate;
2) concentrating to drive off the water; 3) adding an antisolvent to precipitate out the anhydrous form.
53. The process of claim 52 wherein the antisolvent is n-heptane.
54. A process for preparing crystalline Form D of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside hydrate comprising the step of maturating a hydrate or an anhydrate in alcohol/water at an elevated temperature.
55. The process of claim 54 wherein the temperature is above 6O0C.
56. A process for preparing crystalline Form D of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside hydrate comprising the steps of: 1 ) Stirring a suspension of essentially pure 4-[(4-methoxyphenyl)methyl]-5- (trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside in aqueous ethanol; and 2) isolating at an elevated temperature.
57. The process of claim 56 wherein the compound is isolated at a temperature above 6O0C.
58. A process for preparing crystalline Form D of 4-[(4- methoxyphenyl)methyl]-5-(trifluoromethyl)-1 H-pyrazole-3-yl]-4-deoxy-4-fluoro- beta-D-glucopyranoside hydrate comprising the steps of;
1 ) dissolving essentially pure 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)- 1 H-pyrazole-3-yl]-4-deoxy-4-fluoro-beta-D-glucopyranoside in aqueous isopropanol;
2) cooling to crystallize; and 3) isolating at a temperature above 600C.
59. The process of claim 58 wherein the compound is isolated at a temperature above 6O0C.
PCT/US2009/067053 2008-12-08 2009-12-08 Novel polymorphic forms of 4-[(4-methoxyphenyl)methyl]-5-(trifluoromethyl)-1h-pyrazole-3-yl]4-deoxy-4-fluoro-beta-d-glucopyranoside including hydrates thereof and the preparations thereof WO2010068605A1 (en)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
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Publication number Priority date Publication date Assignee Title
US20040259819A1 (en) 2002-12-12 2004-12-23 Aventis Pharma Deutschland Gmbh Novel heterocyclic fluoroglycoside derivatives, medicaments containing these compounds, and the use thereof

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