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WO2016016907A1 - Novel polymorphs of (1s,2s,3r,5s)-3-[7-{[(1r,2s)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3h-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yi]-5-(2-hydroxvethoxy) cyclopentane-1,2-diol - Google Patents

Novel polymorphs of (1s,2s,3r,5s)-3-[7-{[(1r,2s)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3h-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yi]-5-(2-hydroxvethoxy) cyclopentane-1,2-diol Download PDF

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Publication number
WO2016016907A1
WO2016016907A1 PCT/IN2015/000305 IN2015000305W WO2016016907A1 WO 2016016907 A1 WO2016016907 A1 WO 2016016907A1 IN 2015000305 W IN2015000305 W IN 2015000305W WO 2016016907 A1 WO2016016907 A1 WO 2016016907A1
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amino
cyclopropyl
difluorophenyl
pyrimidin
triazolo
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French (fr)
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Srinivasan Thirumalai Rajan
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Satyanarayana Kisara
MSN Laboratories Pvt Ltd
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Satyanarayana Kisara
MSN Laboratories Pvt Ltd
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention provides novel polymorphs of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-
  • Ticagrelor is the first reversibly binding oral adenosine diphosphate (ADP) receptor antagonist and is chemically distinct from thienopyridine compounds like clopidogrel. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events.
  • the drug has shown a statistically significant primary efficacy against the widely prescribed clopidogrel (Plavix) in the prevention of cardiovascular (CV) events including myocardial infarction (heart attacks), stroke, and cardiovascular death in patients with ACS.
  • CV cardiovascular
  • U.S. Patent Application No. 2007/0293513 discloses four crystalline forms (polymorphs I, II, III and IV) of the compound of formula I (ticagrelor), processes for their preparation, and characterizes the polymorphs by powder X-ray diffraction (P-XRD) pattern and melting points which were determined using differential scanning calorimetry (DSC).
  • P-XRD powder X-ray diffraction
  • DSC differential scanning calorimetry
  • the '513 application teaches an amorphous form of ticagrelor (Form a), and a process for preparing it.
  • the ticagrelor in substantially amorphous form is produced by a process which comprises freeze drying or spray drying a solution of ticagrelor using a suitable solvent system, for example ethanol/water.
  • the Form a of ticagrelor is prepared by dissolving ticagrelor in a 50% aqueous solution of ethanol, followed by the drop-wise addition of water and then freeze drying the resulting saturated solution using Virtis instrumentation under the following conditions (vacuum 2170 mT, run time 20.2 hours, condensed temperature -52°C, ambient temperature 20.3°C).
  • Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum.
  • One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) which have been used to distinguish polymorphic forms.
  • TGA thermogravimetric analysis
  • DSC differential scanning calorimetry
  • the present inventors have now surprisingly and unexpectedly found a novel crystalline form of ticagrelor.
  • the novel crystalline form of ticagrelor is consistently reproducible, does not have the tendency to convert to other forms, and is found to be more stable.
  • the novel crystalline form disclosed herein exhibits properties making it suitable for formulating ticagrelor.
  • the first aspect of the present invention is to provide anhydrous crystalline form of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H- [l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l ,2-diol, herein after designated as crystalline form-M.
  • the second aspect of the present invention is to provide crystalline form of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H- [l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol, herein after designated as crystalline form-S.
  • the third aspect of the present invention is to provide process for the preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclo pentane-l,2-diol compound of formula- 1.
  • the fourth aspect of the present invention is to provide a process for the preparation of crystalline form-S of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrirnidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane- 1 ,2-diol compound of formula- 1.
  • Figure-1 Illustrates the PXRD pattern of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-2 Illustrates the DSC endotherm of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-3 Illustrates the IR spectrum of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)- 2-(3 ,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[ 1 ,2,3 ] -triazolo [4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-4 Illustrates the thermogravimetric thermogram of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H- [1,2,3] -triazolo [4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-5 Illustrates the PXRD pattern of crystalline form-S of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Figure-6 Illustrates the PXRD pattern of amorphous form of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)- 2-(3,4-difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
  • Detailed description of the invention :
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2- dimethoxy ethane, tetrahydrofuran and the like; "ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, dioxane and the like; "chloro solvents” such as dichloromethane, dichloroethane, chloroform and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobuty
  • the first aspect of the present invention provides crystalline form-M of (1 S,2S,3R,5S)- 3-[7- ⁇ [(lR,2S)-2-(3,4-difiuorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]- triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula- 1.
  • the crystalline form-M of the present invention is characterized by its powder X- Ray diffraction pattern having peaks at about 4.2, 6.3, 7.0, 8.7, 10.3, 13.0, 17.7, 18.7, 1 .9,
  • the crystalline form-M of the present invention is further characterized by its X-Ray powder diffraction pattern having additional peaks at about 5.4, 8.4, 13.2, 18.0, 19.2, 21.6, 22.0, 22.6, 23.8, 24.6,
  • the crystalline form-M is further characterized by the PXRD pattern as illustrated in figure- 1 and its differential scanning calorimetric (DSC) thermogram having an endofherms at 113.65°C, 138.32°C & 151.94°C as illustrated in figure-2.
  • DSC differential scanning calorimetric
  • the second aspect of the present invention provides crystalline form-S of
  • the crystalline form-S of the present invention is further characterized by its X- ay powder diffraction pattern having additional peaks at about 5.9, 8.4, 11.0, 12.1, 13.5, 16.8, 18.2, 19.5, 21.5, 22.7, 24.1, 25.2, 28.2, 30.0 and 33.1 ⁇ 0.2 degrees of 2-theta.
  • the crystalline form-S is further characterized by the PXRD pattern as illustrated in figure-5.
  • X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used).
  • intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation.
  • persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of the peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used.
  • the skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer.
  • the surface planarity of the sample may also have a small effect.
  • the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a powder diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure.
  • a measurement error of a diffraction angle in an X-ray powder diffraction pattern is typically ⁇ 0.2° of 2-theta.
  • melting point measured by DSC may occur as a result of variations in sample purity, sample preparation and the measurement conditions (e.g. heating rate). It will be appreciated that alternative readings of melting point may be given by other types of equipment or by using conditions different to those described hereinafter. Hence the melting point and endotherm figures quoted herein are not to be taken as absolute values and such measurement errors are to be taken into account when interpreting the DSC data. As a skilled person will realize, melting point can vary with sample purity and degree of crystallinity of the sample. Even low levels of impurities can affect the measured melting point. Therefore, the melting points disclosed herein may vary by ⁇ 5°C from the values quoted herein.
  • the third aspect of the present invention provides a process for the preparation of crystalline form-M of (l S,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l ,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane- 1 ,2-diol compound of formula- 1 , which comprises of:
  • step-c) adding water to the compound obtained in step-c) at a suitable temperature
  • the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, ketone solvents, polar aprotic solvents or mixtures thereof; the suitable temperature is 0°C to reflux temperature of the solvent used in step a);
  • the suitable temperature in steps d), e) & h) are 10-50°C, preferably 25-30°C.
  • the suitable temperature in step i) is 25-60°C, preferably 45-50°C.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2 -hydroxy ethoxy)cyclopentane- 1 ,2-diol compound of formula- 1 , which comprises of:
  • step-c) adding water to the compound obtained in step-c) at 25-30°C j
  • the fourth aspect of the present invention provides a process for the preparation of crystalline form-S of (l S,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane- 1 ,2-diol compound of formula- 1 , which comprises of:
  • step-c) adding water to the compound obtained in step-c) at 25-30°C,
  • the crystalline (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimxdin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane- 1 ,2-diol of the present invention can be utilized in the preparation of pharmaceutical compositions useful for the treatment of arterial thrombosis.
  • the PXRD analysis of the crystalline compound of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A 0 and at a continuous scan speed of 0.03°/min.
  • DSC Differential scanning calorimetric
  • Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • the best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.
  • Example-1 Preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl] amino ⁇ -5-(propylthio)-3H- [1 ,2,3]-triazoIo [4,5-d] pyrimidin- 3-yI]-5-(2-hydroxyethoxy)cycIopentane-l,2-diol (Forniula-l)
  • the PXRD of the obtained compound is shown in figure- 1, the DSC is shown in figure-2 and IR spectrum is shown in figure-3.
  • the termo gravimetric thermogram of the obtained compound shows anhydrous nature of the compound, which is illustrated in figure-4. Yield: 13.0 gm; Water content: 0.02% w/w.
  • Example-3 Preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino ⁇ -5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin- 3-yI]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol (Formula-1)
  • Example-5 Preparation of amorphous (lS,2S,3R,5S)-3-[7- ⁇ [(lR,2S)-2-(3,4-difluoro phenyl)cyclopropyl]amino ⁇ -5-(propyIthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5- (2-ydroxyethoxy)cyclopentane-l,2-diol

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Abstract

The present invention relates to novel polymorphs of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2- (3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidi yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol represented by the following structural formula- 1 and process for its preparation.

Description

Novel polymorphs of gS^S^R.SS^-iT-WlR.ZS't-Z-fS^-difluorophenvn cvclopropyll amino}-5-fpropylthio)-3H-fl,2,31-triazolo[4,5-dlpyrimidin-3-vIl-5-(2-hvdroxyethoxy) cyclopentane-1 ,2-diol Related Applications:
This application claims the benefit of priority of our Indian patent application number 3795/CHE/2014 filed on 1st Aug. 201 which is incorporated herein by reference.
Field of the invention:
The present invention provides novel polymorphs of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-
(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin- 3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol represented by the following structural formula- 1 and process for its preparation.
Figure imgf000002_0001
Formula- 1
Background of the invention:
Ticagrelor is the first reversibly binding oral adenosine diphosphate (ADP) receptor antagonist and is chemically distinct from thienopyridine compounds like clopidogrel. It selectively inhibits P2Y12, a key target receptor for ADP. ADP receptor blockade inhibits the action of platelets in the blood, reducing recurrent thrombotic events. The drug has shown a statistically significant primary efficacy against the widely prescribed clopidogrel (Plavix) in the prevention of cardiovascular (CV) events including myocardial infarction (heart attacks), stroke, and cardiovascular death in patients with ACS.
Various processes for the preparation of ticagrelor, its enantiomers and related compounds, and their pharmaceutically acceptable salts are disclosed in U.S. Patent Nos. 6,251,910; 6,525,060; 6,974,868; 7,067,663; and 7,250,419; U.S. Patent application Nos. 2007/0265282, 2007/0293513 and 2008/0214812; and European Patent Nos. EP0996621 and EP1135391; and PCT Publication Nos. WO2008/018823 and WO2010/030224.
U.S. Patent Application No. 2007/0293513 (hereinafter referred to as the '513 application) discloses four crystalline forms (polymorphs I, II, III and IV) of the compound of formula I (ticagrelor), processes for their preparation, and characterizes the polymorphs by powder X-ray diffraction (P-XRD) pattern and melting points which were determined using differential scanning calorimetry (DSC).
The '513 application teaches an amorphous form of ticagrelor (Form a), and a process for preparing it. According to the teachings of the '513 application, the ticagrelor in substantially amorphous form is produced by a process which comprises freeze drying or spray drying a solution of ticagrelor using a suitable solvent system, for example ethanol/water. As per the process exemplified in the '513 application, the Form a of ticagrelor is prepared by dissolving ticagrelor in a 50% aqueous solution of ethanol, followed by the drop-wise addition of water and then freeze drying the resulting saturated solution using Virtis instrumentation under the following conditions (vacuum 2170 mT, run time 20.2 hours, condensed temperature -52°C, ambient temperature 20.3°C). Polymorphs are distinct solids having the same molecular formula yet having distinct advantageous physical properties compared to other polymorphic forms of the same compound. The difference in the physical properties of different polymorphic forms results from the orientation and intermolecular interactions of adjacent molecules in the bulk solid.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphic forms having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption and solid state NMR spectrum. One polymorphic form may give rise to thermal behavior different from that of another polymorphic form. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) which have been used to distinguish polymorphic forms.
The discovery of new polymorphic form of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product.
There is a strong technical and commercial desire to develop a modified process for the preparation of novel crystalline form of ticagrelor in order to overcome the problems associated with the prior art processes.
The present inventors have now surprisingly and unexpectedly found a novel crystalline form of ticagrelor. The novel crystalline form of ticagrelor is consistently reproducible, does not have the tendency to convert to other forms, and is found to be more stable. The novel crystalline form disclosed herein exhibits properties making it suitable for formulating ticagrelor.
Brief description of the invention:
The first aspect of the present invention is to provide anhydrous crystalline form of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H- [l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l ,2-diol, herein after designated as crystalline form-M.
The second aspect of the present invention is to provide crystalline form of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H- [l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol, herein after designated as crystalline form-S.
The third aspect of the present invention is to provide process for the preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl] amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclo pentane-l,2-diol compound of formula- 1.
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form-S of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrirnidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane- 1 ,2-diol compound of formula- 1.
Brief description of the drawings:
Figure-1: Illustrates the PXRD pattern of crystalline form-M of (lS,2S,3R,5S)-3-[7- {[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
Figure-2: Illustrates the DSC endotherm of crystalline form-M of (lS,2S,3R,5S)-3-[7- {[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
Figure-3: Illustrates the IR spectrum of crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)- 2-(3 ,4-difluorophenyl)cyclopropyl] amino} -5-(propylthio)-3H-[ 1 ,2,3 ] -triazolo [4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
Figure-4: Illustrates the thermogravimetric thermogram of crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H- [1,2,3] -triazolo [4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
Figure-5: Illustrates the PXRD pattern of crystalline form-S of (lS,2S,3R,5S)-3-[7- {[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
Figure-6: Illustrates the PXRD pattern of amorphous form of (lS,2S,3R,5S)-3-[7-{[(lR,2S)- 2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula-1. Detailed description of the invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2- dimethoxy ethane, tetrahydrofuran and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, dioxane and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile and the like; "alcoholic solvents" such as methanol, ethanol, n- propanol, iso-propanol, n-butanol, iso-butanol, t-butanol and the like; "polar solvents" such as water; and/or their mixtures thereof.
The first aspect of the present invention provides crystalline form-M of (1 S,2S,3R,5S)- 3-[7-{[(lR,2S)-2-(3,4-difiuorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]- triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane-l,2-diol compound of formula- 1. The crystalline form-M of the present invention is characterized by its powder X- Ray diffraction pattern having peaks at about 4.2, 6.3, 7.0, 8.7, 10.3, 13.0, 17.7, 18.7, 1 .9,
20.8, 22.3, 23.37, 24.2, 25.1, 27.4, 29.4 and 34.4 ± 0.2 degrees of 2-theta. The crystalline form-M of the present invention is further characterized by its X-Ray powder diffraction pattern having additional peaks at about 5.4, 8.4, 13.2, 18.0, 19.2, 21.6, 22.0, 22.6, 23.8, 24.6,
26.9, 28.3, 31.0 and 35.7 ± 0.2 degrees of 2-theta. The crystalline form-M is further characterized by the PXRD pattern as illustrated in figure- 1 and its differential scanning calorimetric (DSC) thermogram having an endofherms at 113.65°C, 138.32°C & 151.94°C as illustrated in figure-2.
The crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxy ethoxy)cyclopentane-l ,2-diol compound of formula- 1 is further characterized by its IR absorption spectrum having absorption bands at 3406, 3292, 2931, 1625, 1590, 1521, 1455, 1428, 1329, 1210, 1097, 1051, 993 and 772 cm"1, as illustrated in figure-3.
The second aspect of the present invention provides crystalline form-S of
(lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-
[1 ,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l ,2-dioI compound of formula- 1. The crystalline form-S of the present invention is characterized by its powder X-Ray diffraction pattern having peaks at about 3.9, 5.2, 6.4, 7.9, 9.8, 11.8, 15.0, 15.9, 17.8,
18.9, 21.0, 22.6, 23.3, 24.8, 25.3, 27.6, 29.5 and 33.1 ± 0.2 degrees of 2-theta. The crystalline form-S of the present invention is further characterized by its X- ay powder diffraction pattern having additional peaks at about 5.9, 8.4, 11.0, 12.1, 13.5, 16.8, 18.2, 19.5, 21.5, 22.7, 24.1, 25.2, 28.2, 30.0 and 33.1 ± 0.2 degrees of 2-theta. The crystalline form-S is further characterized by the PXRD pattern as illustrated in figure-5.
It is known in the art that X-ray powder diffraction pattern may be obtained which has one or more measurement errors depending on measurement conditions (such as equipment, sample preparation or machine used). In particular, it is generally known that intensities in an X-ray powder diffraction pattern may fluctuate depending on measurement conditions and sample preparation. For example, persons skilled in the art of X-ray powder diffraction will realize that the relative intensities of the peaks may vary according to the orientation of the sample under test and on the type and setting of the instrument used. The skilled person will also realize that the position of reflections can be affected by the precise height at which the sample sits in the diffractometer and the zero calibration of the diffractometer. The surface planarity of the sample may also have a small effect. Hence a person skilled in the art will appreciate that the diffraction pattern data presented herein is not to be construed as absolute and any crystalline form that provides a powder diffraction pattern substantially identical to those disclosed herein fall within the scope of the present disclosure.
Generally, a measurement error of a diffraction angle in an X-ray powder diffraction pattern is typically ± 0.2° of 2-theta.
A person skilled in the art will also appreciate that slight variations in the melting point measured by DSC may occur as a result of variations in sample purity, sample preparation and the measurement conditions (e.g. heating rate). It will be appreciated that alternative readings of melting point may be given by other types of equipment or by using conditions different to those described hereinafter. Hence the melting point and endotherm figures quoted herein are not to be taken as absolute values and such measurement errors are to be taken into account when interpreting the DSC data. As a skilled person will realize, melting point can vary with sample purity and degree of crystallinity of the sample. Even low levels of impurities can affect the measured melting point. Therefore, the melting points disclosed herein may vary by ± 5°C from the values quoted herein. The third aspect of the present invention provides a process for the preparation of crystalline form-M of (l S,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[l ,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane- 1 ,2-diol compound of formula- 1 , which comprises of:
a) Dissolving (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5- (propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane- 1 ,2-diol compound of formula- 1 in a suitable solvent at a suitable temperature, b) filtering the reaction mixture,
c) distilling off the solvent completely under reduced pressure,
d) adding water to the compound obtained in step-c) at a suitable temperature,
e) stirring the reaction mixture at a suitable temperature,
f) decanting the aqueous layer,
g) adding water to the compound obtained in step f),
h) stirring the reaction mixture at a suitable temperature,
i) filtering the precipitated solid, washing with water and drying the compound at a suitable temperature to provide crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4- difluoropheny l)cy clopropy 1] amino } -5 -( ro^
yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
Wherein in step a) the suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, nitrile solvents, ketone solvents, polar aprotic solvents or mixtures thereof; the suitable temperature is 0°C to reflux temperature of the solvent used in step a);
The suitable temperature in steps d), e) & h) are 10-50°C, preferably 25-30°C.
The suitable temperature in step i) is 25-60°C, preferably 45-50°C. The preferred embodiment of the present invention provides a process for the preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2 -hydroxy ethoxy)cyclopentane- 1 ,2-diol compound of formula- 1 , which comprises of:
a) Dissolving (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5- (propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane- 1 ,2-diol compound of formula- 1 in dichloromethane,
b) filtering the reaction mixture,
c) distilling off the solvent completely under reduced pressure,
d) adding water to the compound obtained in step-c) at 25-30°Cj
e) stirring the reaction mixture for 30 minutes at 25-30°C,
f) decanting the aqueous layer,
g) adding water to the compound obtained in step f),
h) stirring the reaction mixture for 1 hour at 25-30°C,
i) filtering the precipitated solid, washing with water and drying the compound at 45-50°C to provide crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2- hydroxyethoxy)cyclopentane- 1 ,2-diol compound of formula- 1.
The fourth aspect of the present invention provides a process for the preparation of crystalline form-S of (l S,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane- 1 ,2-diol compound of formula- 1 , which comprises of:
a) Dissolving (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5- (propylthio)-3H-[l,2,3]-triazolo[455-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)
cyclopentane- 1 ,2-diol compound of formula- 1 in methanol,
b) filtering the reaction mixture,
c) distilling off the solvent completely under reduced pressure,
d) adding water to the compound obtained in step-c) at 25-30°C,
e) stirring the reaction mixture for 30 minutes at 25-30°C,
f) decanting the aqueous layer,
g) adding water to the compound obtained in step f),
h) stirring the reaction mixture for 1 hour at 25-30°C,
i) filtering the precipitated solid, washing with water and aerial drying the compound at 25- 30°C to provide crystalline form-S of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3- yl] -5 -(2 -hydroxyethoxy)cyclopentane- 1,2-diol compound of formula-1.
The (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}- 5-(propylthio)-3H-[l ,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane- 1 ,2-diol utilized in step-a) of the third & fourth aspects as well as . in the preparation of amorphous form can be synthesized by any of the prior known processes described in the art.
The crystalline Form-M & Form-S of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3s4- difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]- 5-(2-hydroxyethoxy)cyclopentane-l,2-diol compound of formula-1 of the present invention is stable at room temperature.
The crystalline (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimxdin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane- 1 ,2-diol of the present invention can be utilized in the preparation of pharmaceutical compositions useful for the treatment of arterial thrombosis.
The PXRD analysis of the crystalline compound of the present invention was carried out using BRUKER/AXS X-Ray diffractometer using CuKa radiation of wavelength 1.5406 A0 and at a continuous scan speed of 0.03°/min.
Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C/min.
(lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propyl thio)-3H-[ 1 ,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-ydroxyethoxy)cyclopentane- 1 ,2-diol produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product. The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H- [1 ,2,3]-triazoIo [4,5-d] pyrimidin- 3-yI]-5-(2-hydroxyethoxy)cycIopentane-l,2-diol (Forniula-l)
Dissolve 15 gms of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxy ethoxy)cyclopentane-l,2-diol in 60 ml of dichloromethane at 35-40°C. Filtered the reaction mixture and distilled off the solvent from the filtrate under reduced pressure. 45 ml of water was added to the obtained compound at 25-30°C. Stirred the reaction mixture for 30 minutes at the same temperature and the decanted the aqueous layer. 45 ml of water was added to the obtained reaction mixture at 25-30°C and stirred the resulting mixture for 1 hour at the same temperature. Filtered the solid and washed with water. Dried the obtained material at 45-50°C to get the title compound.
The PXRD of the obtained compound is shown in figure- 1, the DSC is shown in figure-2 and IR spectrum is shown in figure-3. The termo gravimetric thermogram of the obtained compound shows anhydrous nature of the compound, which is illustrated in figure-4. Yield: 13.0 gm; Water content: 0.02% w/w.
ExampIe-2: Preparation of crystalline form-S of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin- 3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol (Formula-1)
Dissolve 15 gms of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-( ropylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane-l,2-diol in 60 ml of methanol at 25-30°C. Filtered the reaction mixture and distilled off the solvent from the filtrate under reduced pressure. 45 ml of water was added to the obtained compound at 25-30°C. Stirred the reaction mixture for 30 minutes at the same temperature and the decanted the aqueous layer. 45 ml of water was added to the obtained reaction mixture at 25-30°C and stirred the resulting mixture for 1 hour at the same temperature. Filtered the solid and washed with water. Dried the obtained material under aerial drying conditions (i.e. at 25-30°C) to get the title compound.
The PXRD of the obtained compound is shown in figure-5.
Yield: 12.5 gm; Water content: 2.0 % w/w.
Example-3: Preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin- 3-yI]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol (Formula-1)
20 gms of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}- 5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane- 1,2-diol was added to 60 ml of water at 25-30°C. Stirred the reaction mixture for 30 minutes at the same temperature and the decanted the aqueous layer. 60 ml of water was added to the obtained reaction mixture at 25-30°C and stirred the resulting mixture for 1 hour at the same temperature. Filtered the solid and washed with water. Dried the obtained material at 45-50°C to get the title compound.
The PXRD of the obtained compound is shown in figure- 1.
Yield: 17.5 gm
ExampIe-4: Preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4- difiuorophenyl)cyclopropyI]amino}-5-(propyIthio)-3H-[l,2,3J-triazoIo[4,5-d]pyrimidin- 3-yI]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol (Formula-1)
20 gms of amorphous (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxy ethoxy)cyclopentane-l,2-diol was added to 60 ml of water at 25-30°C. Stirred the reaction mixture for 30 minutes at the same temperature and the decanted the aqueous layer. 60 ml of water was added to the obtained reaction mixture at 25-30°C and stirred the resulting mixture for 1 hour at the same temperature. Filtered the solid and washed with water. Dried the obtained material at 45-50°C to get the title compound. The PXRD of the obtained compound is shown in figure- 1.
Yield: 17.9 gm.
Example-5: Preparation of amorphous (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluoro phenyl)cyclopropyl]amino}-5-(propyIthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5- (2-ydroxyethoxy)cyclopentane-l,2-diol
Dissolve 50 gms of (l S,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[l ,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane-l,2-diol in a mixture of dichloromethane (225 ml) and methanol (25 ml) at 25-30°C. Filtered the reaction mixture and washed with mixture of dichloromethane (90 ml) and methanol (10 ml). Distilled off the solvent from the filtrate atmospherically and finally vacuum was applied for 3-4 hours. 200 ml of n-heptane is added at 25-30°C and stirred the reaction mixture for 45 minutes at the same temperature. Filtered the solid and washed with n- heptane. Dried the material to get title compound.
The PXRD of the obtained compound is shown in figure-6.
Yield: 48.0 gm.
Particle size distribution before micronization: D90: 80.6 μηι;
Particle size distribution after micronization: D90: 7.70 μτη;

Claims

We Claim:
Γ. Crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy cyclopentane-l ,2-diol, characterized by;
a) Its powder X-Ray diffraction pattern having characteristic peaks at 4.2, 6.3, 7.0, 8.7, 10.3, 13.0, 17.7, 18.7, 19.9, 20.8, 22.3, 23.37, 24.2, 25.1, 27.4, 29.4 and 34.4 ± 0.2 degrees of 2-theta, and the powder X-Ray diffraction pattern substantially as illustrated in figure- 1,
b) its differential scanning calorimetric (DSC) thermogram having an endotherms at 113.65°C, 138.32°C & 151.94°C substantially in accordance with figure-2.
2. Crystalline form-M of (l S,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol, is further characterized by its powder X-Ray diffraction pattern having characteristic peaks at 5.4, 8.4, 13.2, 18.0, 19.2, 21.6, 22.0, 22.6, 23.8, 24.6, 26.9, 28.3, 31.0 and 35.7 ± 0.2 degrees of 2-theta.
3. Crystalline form-S of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol, characterized by its powder X-Ray diffraction pattern having characteristic peaks at 3.9, 5.2, 6.4, 7.9, 9.8, 11.8, 15.0, 15.9, 17.8, 18.9, 21.0, 22.6, 23.3, 24.8, 25.3, 27.6, 29.5 and 33.1 ± 0.2 degrees of 2-theta, and the powder X-Ray diffraction pattern substantially as illustrated in figure-5.
4. Crystalline form-S of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-(propylthio)-3H-[l ,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol, is further characterized by its powder X-Ray diffraction pattern having characteristic peaks at 5.9, 8.4, 11.0, 12.1, 13.5, 16.8, 18.2, 19.5, 21.5, 22.7, 24.1, 25.2, 28.2, 30.0 and 33.1 ± 0.2 degrees of 2-theta.
5. A process for the preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-
(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol comprising of;
a) Dissolving (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}- 5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclo pentane-l,2-diol compound of formula- 1 in a suitable solvent at a suitable temperature,
b) filtering the reaction mixture,
c) distilling off the solvent completely under reduced pressure,
d) adding water to the compound obtained in step-c) at a suitable temperature, e) stirring the reaction mixture at a suitable temperature,
f) decanting the aqueous layer,
g) adding water to the compound obtained in step f),
h) stirring the reaction mixture at a suitable temperature,
i) filtering the precipitated solid, washing with water and drying the compound at a suitable temperature to provide crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)- 2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
A process according to claim-5, wherein,
step a) the suitable solvent is selected from chloio solvents, alcohol solvents, ester solvents, nitrile solvents, ketone solvents, polar aprotic solvents or mixtures thereof; the suitable temperature is 0°C to reflux temperature of the solvent used in step a);
the suitable temperature in steps d), e) & h) are 10-50°C, preferably 25-30°C.
the suitable temperature in step i) is 25-60°C, preferably 45-50°C.
A process for the preparation of crystalline form-M of (l S,2S,3R,5S)-3-[7-{[(lR,2S)-2- (3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol comprising of;
a) Dissolving (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}- 5-^ropylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol compound of formula-1 in dichloromethane,
b) filtering the reaction mixture, c) distilling off the solvent completely under reduced pressure,
d) adding water to the compound obtained in step-c) at 25-30°C,
e) stirring the reaction mixture for 30 minutes at 25-30°C,
f) decanting the aqueous layer,
g) adding water to the compound obtained in step f),
h) stirring the reaction mixture for 1 hour at 25-30°C,
i) filtering the precipitated solid, washing with water and drying the compound at 45- 50°C to provide crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4- difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol compound of formula- 1.
A process for the preparation of crystalline form-S of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2- (3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol comprising of;
a) Dissolving (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}- 5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-1 ,2-diol compound of formula-1 in methanol,
b) filtering the reaction mixture,
c) distilling off the solvent completely under reduced pressure,
d) adding water to the compound obtained in step-c) at 25-30°C,
e) stirring the reaction mixture for 30 minutes at 25-30°C,
f) decanting the aqueous layer,
g) adding water to the compound obtained in step f),
h) stirring the reaction mixture for 1 hour at 25-30°C,
i) filtering the precipitated solid, washing with water and drying the compound under aerial drying conditions to provide crystalline form-S of (lS,2S,3R,5S)-3-[7- {[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]- triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol compound of formula-1.
A process for the preparation of crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2- (3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol comprising of;
a) Adding water to (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl)cyclopropyl] amino}-5-( ropylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol compound of formula- 1,
b) stirring the reaction mixture,
c) decanting the aqueous layer,
d) adding water to the compound obtained in step c),
e) stirring the reaction mixture,
f) filtering the precipitated solid, washing with water and drying the compound to provide crystalline form-M of (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3-yI]-5-(2- hydroxyethoxy)cyclopentane- 1 ,2-diol compound of formula- 1.
10. Particle size distribution of amorphous compound of formula- 1 obtained according to the present invention is having D90 less than 500 μη .
1 1. A pharmaceutical composition comprising crystalline (lS,2S,3R,5S)-3-[7-{[(lR,2S)-2- (3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d] pyrimidin-3-yl]-5-(2-hydroxyethoxy) cyclopentane-l,2-diol according to claims 1 to 4 and at least one pharmaceutically acceptable excipient.
12. Use of crystalline Form-M & Form-S of (18,28,3^58)-3-[7-{[(1^28)-2-(3,4- difluorophenyl)cyclopropyl]amino}-5-( ropylthio) H-[l,2,3] riazolo[4,5-d]pyrimidin-3- yl]-5-(2-hydroxyethoxy)cyclopentane-l,2-diol compound of formula- 1 in the preparation of pharmaceutical composition.
*******
PCT/IN2015/000305 2014-08-01 2015-07-31 Novel polymorphs of (1s,2s,3r,5s)-3-[7-{[(1r,2s)-2-(3,4-difluorophenyl) cyclopropyl]amino}-5-(propylthio)-3h-[1,2,3]-triazolo[4,5-d]pyrimidin-3-yi]-5-(2-hydroxvethoxy) cyclopentane-1,2-diol Ceased WO2016016907A1 (en)

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IN3795/CHE/2014 2014-08-01

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092262A1 (en) * 2000-06-02 2001-12-06 Astrazeneca Ab New crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound
WO2013079589A1 (en) * 2011-11-30 2013-06-06 Actavis Group Ptc Ehf Novel crystalline form of ticagrelor and process for the preparation thereof
WO2014166337A1 (en) * 2013-04-07 2014-10-16 杭州领业医药科技有限公司 Crystalline form of ticagrelor and manufacturing method and usage thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001092262A1 (en) * 2000-06-02 2001-12-06 Astrazeneca Ab New crystalline and amorphous form of a triazolo(4,5-d)pyrimidine compound
WO2013079589A1 (en) * 2011-11-30 2013-06-06 Actavis Group Ptc Ehf Novel crystalline form of ticagrelor and process for the preparation thereof
WO2014166337A1 (en) * 2013-04-07 2014-10-16 杭州领业医药科技有限公司 Crystalline form of ticagrelor and manufacturing method and usage thereof

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