WO2016008461A1 - A new form of sofosbuvir and a method of its preparation - Google Patents

A new form of sofosbuvir and a method of its preparation Download PDF

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Publication number
WO2016008461A1
WO2016008461A1 PCT/CZ2015/000078 CZ2015000078W WO2016008461A1 WO 2016008461 A1 WO2016008461 A1 WO 2016008461A1 CZ 2015000078 W CZ2015000078 W CZ 2015000078W WO 2016008461 A1 WO2016008461 A1 WO 2016008461A1
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Prior art keywords
sofosbuvir
accordance
solvent
crystalline form
ester
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PCT/CZ2015/000078
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French (fr)
Inventor
Martin STEFKO
Ondrej Dammer
Lukas KREJCIK
Stanislav MAN
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Zentiva, K.S.
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Priority to EP15747360.4A priority Critical patent/EP3169692A1/en
Publication of WO2016008461A1 publication Critical patent/WO2016008461A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives

Definitions

  • the invention relates to a new crystalline form of SOFOSBUVIR of formula (I), chemically isopropyl ((S)-(((2R 5 3R,4R i 5R)-5-(2,4-dioxo-3 ,4-dihydropyrimidin-l (2H)-yl)-4-fluoro-3- hydroxy-4-metiLyltetrahydrofur ⁇ and a method for the preparation thereof.
  • Sofosbuvir is a compound designed for treatment of hepatitis C infection.
  • the compound was first described in the patent application WO2008121634; a general preparation procedure of this compound and a number of other compounds with a similar composition are included in the above mentioned application on pages 668 to 671.
  • the synthesis is further documented in examples 13 to 66. Reproduction of these procedures provided sofosbuvir in an amorphous form (foam or oil form).
  • SOFOSBUVIR is a so-called prodrug, which is easily enzymatically transformed directly in the liver to the active substance 2'-deoxy-2'-a-fiuoro- -C-metbyluridine-5'-triphosphate, which serves as an RNA polymerase inhibitor (NS5B protein), inhibiting the synthesis of viral RNA.
  • Sofosbuvir represents the first non-interferon treatment of chronic hepatitis C with the cure rate of up to 90%.
  • the patent application WO2010/135569 describes preparation and characterization of five polymorphs and an amorphous form of Sofosbuvir, while the application WO2011/123645 adds form VI to this list.
  • Form VI is prepared by crystallization from an aqueous solution, but it is surprisingly non-hygroscopic and stable when exposed to the air.
  • Forms V and IV are prepared by crystallization from anisole and acetonitrile. However, both of them pass to Form I by mere filtration.
  • Form III is described as a 1 :1 solvate with chloroform, while form II is a 1:1 solvate with dichloromethane.
  • Form I represents a non- solvated form of Sofosbuvir.
  • the patent further describes single crystal X-ray crystallographic data of Forms I, II, III.
  • the invention provides a new polymorphic form of Sofosbuvir Z-l, its preparation and characterization.
  • the prepared polymorphic form exhibits a high physical stability, which makes it a suitable candidate for use in a pharmaceutical composition.
  • Fig. 1 IR spectrum of Sofosbuvir, Form Z-l .
  • Fig.2 RAMAN spectrum of Sofosbuvir, Form Z-l .
  • Fig. 3 Solid phase 13 C ssNMR of SOFOSBUVIR, Form Z-l .
  • Fig. 4 Solid phase 19 F ssNMR of Sofosbuvir Form Z-l.
  • Fig. 5 X-ray powder pattern of Sofosbuvir Form Z-l .
  • Fig. 6 DVS curve of Sofosbuvir Form Z-l .
  • the invention provides a new polymorphic form of Sofosbuvir, referred to as Z-l, which has not been described in literature yet.
  • the main advantage of this new polymorphic form consists in its better purification abilities as compared to the existing described form 1 (WO2011/123645).
  • This form is anhydrous, non-hygroscopic and appears to be chemically and polymorphously stable.
  • Form Z-l has been characterized with the use of the following analytic methods: X-Ray powder diffraction (XRPD), Raman spectroscopy, IR spectroscopy, NMR spectroscopy and dynamic vapour sorption (DVS).
  • Sofosbuvir (I) obtained in accordance with the patent O2011/123645 (FORM I) exhibits max. 98.0% purity (according to HPLC). Crystallization from a mixture of DCM/toluene according to the said patent application, as well as repeated crystallization for this mixture, does not virtually lead to any further purification. It is obvious that repeated crystallization does not lead to a reduction of the contents of impurities below the defined limits (0.10 and 0.15%). Such raw material is then not suitable for pharmaceutical production.
  • Form Z-l of Sofosbuvir in accordance with this invention is characterized by the following reflections in an X-ray powder pattern: 8.0; 12.3; 17.1; 19.9 and 20.8 ⁇ 0.2° 2-theta with the use of CuKa radiation. Still, more diffraction peaks can be found in the X-ray powder pattern: 10.3; 13.4; 16.1; 17.9; 19.3; 23.6; 24.8 and 27.0 ⁇ 0.2° 2-theta.
  • Table 1 An X-ray powder pattern of this polymorphic form is shown in Figure 5.
  • Form Z-l of Sofosbuvir in accordance with this invention is characterized by the following reflection bands in the FTIR spectrum: 3251, 1719, 1669, 1265, 1092 and 945 + 4 cm “1 (Fig. 1).
  • Form Z-l of Sofosbuvir in accordance with this invention is characterized by the following maximum intensity bands in the FT-Raman spectrum: 2987, 1718, 1671, 1373, 1217, 1007, 774 ⁇ 4 cn 1 (Fig. 2).
  • Form Z-l of Sofosbuvir in accordance with this invention is further characterized with solid phase 13 C and 19 F ssNMR.
  • a solid phase 13 C ssNMR spectrum of this polymorphic form is shown in Figure 3.
  • a solid phase 19 F ssNMR spectrum of this polymorphic form is shown in Figure 4.
  • the dynamic vapour sorption record indicates stability of the polymorph in the range of 0 to 70% of relative humidity, where the water content increase in the sample has been in the range of 0 to 0.4%.
  • the relative humidity interval of 70-90% a significant increase of water sorption from 0.4 to 6.4% has been registered.
  • a subsequent reversal of the cycle (desorption) and reduction of relative humidity from 90% does not change the water content, which remains to be 6.4%.
  • 60% relative humidity is achieved, abrupt desorption of water occurs, the water content dropping to 0.4% at 50% relative humidity, while the water content further slowly decreases down to 0% at 0% relative humidity.
  • a subsequently repeated sorption/desorption process follows the above mentioned course.
  • Form Z-l is stable and resistant to humidity when exposed to the air.
  • the invention also includes a method for the preparation of the new Form Z-l.
  • Form Z-l can be obtained by crystallization of Sofosbuvir from an ester of a C3 to C5 alcohol and CI to C4 acids.
  • the ester is preferably selected such that the total number of carbon atoms be 5 to 8.
  • Propyl ester of butanoic acid or pentyl ester of formic acid thus appear to be convenient.
  • the ester may be composed of primary, secondary or tertiary alcohols.
  • the carbon skeleton of the acid may be linear or branched.
  • esters may be used either pure or in a mixture with another solvent, a so-called co-solvent. Less polar solvents are selected as the co-solvents.
  • co-solvents For example, C6 to C9 aromatics, or C6 to C9 alicyclic hydrocarbons, or CI to C4 chlorinated hydrocarbons, substituted with one or more chlorine atoms have proved to be suitable.
  • An example may be cyclohexane, toluene or DCM.
  • the new polymorphic Form Z-1 of Sofosbuvir exhibits 99.8% purity after the first crystallization from a mixture of n-butyl acetate/toluene already; the subsequent re- crystallization provides a product with 99.9% purity, while all the detected impurities are below the defined limit values (0.10 and 0.15%).
  • the quality of the API prepared this way meets the requirements for pharmaceutical use.
  • n-butyl acetate as the solvent in the preparation process of this new polymorphic Form Z-1 of Sofosbuvir.
  • This solvent is non-toxic with the limit of 5000 ppm for the final API, involatile (boiling temperature 126°C) and it does not produce explosive vapour. This makes it a suitable solvent for possible industrial production of Sofosbuvir.
  • the measurement was carried out with a flat powder sample applied onto a Si plate.
  • a 10mm mask and a 1/4° fixed anti- dispersion slit were used.
  • the irradiated area of the sample was 10 mm, programmable divergence slits were used.
  • For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used.
  • the ATR(ZnSe)-FTIR spectra were measured using a FTIR Nicolet Nexus spectrometer (Thermo, USA). 12 scans with the resolution of 4 cm "1 were applied to one spectrum.
  • FT-Raman spectra were measured using a RFS 100/S FTIR spectrometer (Bruker, Germany). 128 scans with the resolution of 4 cm “1 were applied to one spectrum. A laser device with the wavelength of 1064 nm and the output of 250 mW was used as the source of excitation radiation.
  • NMR spectra were measured with an Avance 500 device by Bruker. 1H spectra were measured at the frequency of 500.13 MHz, 13 C at the frequency of 125.8 MHz. The sample was measured in a deuterated solvent specified for the particular analysis, normally at 25°C (unless specified otherwise for a particular analysis). The chemical shift ⁇ is expressed in ppm units, interaction constants J in Hz. The spectra were normally referenced to the residual solvent content.
  • Solid state NMR spectra were measured using a Bruker Avance III 400 WB spectrometer.
  • I3 C CP MAS experiments were measured with a 4-mm probe with the rotation rate of 13 kHz, contact time 2 ms
  • the dynamic vapour sorption (DVS) patterns were measures with a DVS Advantage 1 device made by the company Surface Measurement Systems.
  • the sample charge in a quartz pot was 20.2 mg and the temperature in the device was 25.4°C.

Abstract

The crystalline Form Z-1 of sofosbuvir, characterized by the following diffraction peaks: 8.0; 12.3; 17.1; 19.9 and 20.8 ±0,2° 2-theta with the use of CuKα radiation, and a method of its preparation.

Description

A new form of Sofosbuvir and a method of its preparation Technical Field
The invention relates to a new crystalline form of SOFOSBUVIR of formula (I), chemically isopropyl ((S)-(((2R53R,4Ri5R)-5-(2,4-dioxo-3 ,4-dihydropyrimidin-l (2H)-yl)-4-fluoro-3- hydroxy-4-metiLyltetrahydrofur^ and a method for the preparation thereof.
Figure imgf000002_0001
Background Art
Sofosbuvir is a compound designed for treatment of hepatitis C infection. The compound was first described in the patent application WO2008121634; a general preparation procedure of this compound and a number of other compounds with a similar composition are included in the above mentioned application on pages 668 to 671. The synthesis is further documented in examples 13 to 66. Reproduction of these procedures provided sofosbuvir in an amorphous form (foam or oil form).
SOFOSBUVIR is a so-called prodrug, which is easily enzymatically transformed directly in the liver to the active substance 2'-deoxy-2'-a-fiuoro- -C-metbyluridine-5'-triphosphate, which serves as an RNA polymerase inhibitor (NS5B protein), inhibiting the synthesis of viral RNA. Sofosbuvir represents the first non-interferon treatment of chronic hepatitis C with the cure rate of up to 90%.
The patent application WO2010/135569 describes preparation and characterization of five polymorphs and an amorphous form of Sofosbuvir, while the application WO2011/123645 adds form VI to this list. Form VI is prepared by crystallization from an aqueous solution, but it is surprisingly non-hygroscopic and stable when exposed to the air. Forms V and IV are prepared by crystallization from anisole and acetonitrile. However, both of them pass to Form I by mere filtration. Form III is described as a 1 :1 solvate with chloroform, while form II is a 1:1 solvate with dichloromethane. Form I represents a non- solvated form of Sofosbuvir. The patent further describes single crystal X-ray crystallographic data of Forms I, II, III.
Disclosure of Invention
The invention provides a new polymorphic form of Sofosbuvir Z-l, its preparation and characterization. The prepared polymorphic form exhibits a high physical stability, which makes it a suitable candidate for use in a pharmaceutical composition.
Brief Description of Drawings
Fig. 1: IR spectrum of Sofosbuvir, Form Z-l .
Fig.2: RAMAN spectrum of Sofosbuvir, Form Z-l .
Fig. 3: Solid phase 13C ssNMR of SOFOSBUVIR, Form Z-l .
Fig. 4: Solid phase 19F ssNMR of Sofosbuvir Form Z-l.
Fig. 5: X-ray powder pattern of Sofosbuvir Form Z-l .
Fig. 6: DVS curve of Sofosbuvir Form Z-l .
Detailed description of the invention
The invention provides a new polymorphic form of Sofosbuvir, referred to as Z-l, which has not been described in literature yet. The main advantage of this new polymorphic form consists in its better purification abilities as compared to the existing described form 1 (WO2011/123645). This form is anhydrous, non-hygroscopic and appears to be chemically and polymorphously stable. Form Z-l has been characterized with the use of the following analytic methods: X-Ray powder diffraction (XRPD), Raman spectroscopy, IR spectroscopy, NMR spectroscopy and dynamic vapour sorption (DVS).
Sofosbuvir (I) obtained in accordance with the patent O2011/123645 (FORM I) exhibits max. 98.0% purity (according to HPLC). Crystallization from a mixture of DCM/toluene according to the said patent application, as well as repeated crystallization for this mixture, does not virtually lead to any further purification. It is obvious that repeated crystallization does not lead to a reduction of the contents of impurities below the defined limits (0.10 and 0.15%). Such raw material is then not suitable for pharmaceutical production. Form Z-l of Sofosbuvir in accordance with this invention is characterized by the following reflections in an X-ray powder pattern: 8.0; 12.3; 17.1; 19.9 and 20.8 ± 0.2° 2-theta with the use of CuKa radiation. Still, more diffraction peaks can be found in the X-ray powder pattern: 10.3; 13.4; 16.1; 17.9; 19.3; 23.6; 24.8 and 27.0 ± 0.2° 2-theta. The positions of the diffraction peaks and the interplanar spacings and relative intensities corresponding to them are summarized in Table 1. An X-ray powder pattern of this polymorphic form is shown in Figure 5.
Table 1. Typical diffraction peaks corresponding to Sofosbuvir Form Z-l
Figure imgf000004_0001
Form Z-l of Sofosbuvir in accordance with this invention is characterized by the following reflection bands in the FTIR spectrum: 3251, 1719, 1669, 1265, 1092 and 945 + 4 cm"1 (Fig. 1). Form Z-l of Sofosbuvir in accordance with this invention is characterized by the following maximum intensity bands in the FT-Raman spectrum: 2987, 1718, 1671, 1373, 1217, 1007, 774 ± 4 cn 1 (Fig. 2).
Form Z-l of Sofosbuvir in accordance with this invention is further characterized with solid phase 13C and 19F ssNMR. A solid phase 13C ssNMR spectrum of this polymorphic form is shown in Figure 3. A solid phase 19F ssNMR spectrum of this polymorphic form is shown in Figure 4.
Solution 1H NMR spectra and I3C ssNMR have not confirmed the presence of a solvate and ssNMR spectroscopy has not confirmed the presence of a cocrystal either.
19F ssNMR provides another characteristic of the new crystalline form with a single peak at the chemical shift δ of 154.66 ppm.
The dynamic vapour sorption record indicates stability of the polymorph in the range of 0 to 70% of relative humidity, where the water content increase in the sample has been in the range of 0 to 0.4%. In the relative humidity interval of 70-90% a significant increase of water sorption from 0.4 to 6.4% has been registered. A subsequent reversal of the cycle (desorption) and reduction of relative humidity from 90% does not change the water content, which remains to be 6.4%. When 60% relative humidity is achieved, abrupt desorption of water occurs, the water content dropping to 0.4% at 50% relative humidity, while the water content further slowly decreases down to 0% at 0% relative humidity. A subsequently repeated sorption/desorption process follows the above mentioned course.
Form Z-l is stable and resistant to humidity when exposed to the air.
The invention also includes a method for the preparation of the new Form Z-l. Form Z-l can be obtained by crystallization of Sofosbuvir from an ester of a C3 to C5 alcohol and CI to C4 acids. The ester is preferably selected such that the total number of carbon atoms be 5 to 8. Propyl ester of butanoic acid or pentyl ester of formic acid thus appear to be convenient. The ester may be composed of primary, secondary or tertiary alcohols. Similarly, the carbon skeleton of the acid may be linear or branched.
The ester of acetic acid with n-butanol (n-butyl acetate) appears to be the best solution. The above mentioned esters may be used either pure or in a mixture with another solvent, a so-called co-solvent. Less polar solvents are selected as the co-solvents. For example, C6 to C9 aromatics, or C6 to C9 alicyclic hydrocarbons, or CI to C4 chlorinated hydrocarbons, substituted with one or more chlorine atoms have proved to be suitable. An example may be cyclohexane, toluene or DCM.
The new polymorphic Form Z-1 of Sofosbuvir exhibits 99.8% purity after the first crystallization from a mixture of n-butyl acetate/toluene already; the subsequent re- crystallization provides a product with 99.9% purity, while all the detected impurities are below the defined limit values (0.10 and 0.15%). The quality of the API prepared this way meets the requirements for pharmaceutical use.
Another advantage is the use of n-butyl acetate as the solvent in the preparation process of this new polymorphic Form Z-1 of Sofosbuvir. This solvent is non-toxic with the limit of 5000 ppm for the final API, involatile (boiling temperature 126°C) and it does not produce explosive vapour. This makes it a suitable solvent for possible industrial production of Sofosbuvir.
The invention is clarified in a more detailed way using the working example below. The example, which illustrates the improvement of the procedure in accordance with the invention, only has an illustrative character and does not restrict the scope of the invention in any respect.
Experimental part: Analytical methods:
X-ray powder diffraction
The diffractograms were obtained using an X'PE T PRO PD PANaiytical powder diffractometer, used radiation CuKa (λ=1.542 A), excitation voltage: 45 kV, anode current: 40 mA, measured range: 2 - 40° 2Θ, increment: 0.01° 2Θ at the dwell time at a reflection of 50 s. The measurement was carried out with a flat powder sample applied onto a Si plate. For the correction of the primary array 0.02 rad Soller slits, a 10mm mask and a 1/4° fixed anti- dispersion slit were used. The irradiated area of the sample was 10 mm, programmable divergence slits were used. For the correction of the secondary array 0.02 rad Soller slits and a 5.0 anti-dispersion slit were used.
IR
The ATR(ZnSe)-FTIR spectra were measured using a FTIR Nicolet Nexus spectrometer (Thermo, USA). 12 scans with the resolution of 4 cm"1 were applied to one spectrum.
Raman:
FT-Raman spectra were measured using a RFS 100/S FTIR spectrometer (Bruker, Germany). 128 scans with the resolution of 4 cm"1 were applied to one spectrum. A laser device with the wavelength of 1064 nm and the output of 250 mW was used as the source of excitation radiation.
Nuclear magnetic resonance (NMR)
NMR spectra were measured with an Avance 500 device by Bruker. 1H spectra were measured at the frequency of 500.13 MHz, 13C at the frequency of 125.8 MHz. The sample was measured in a deuterated solvent specified for the particular analysis, normally at 25°C (unless specified otherwise for a particular analysis). The chemical shift δ is expressed in ppm units, interaction constants J in Hz. The spectra were normally referenced to the residual solvent content.
Solid state NMR spectra were measured using a Bruker Avance III 400 WB spectrometer. I3C CP MAS experiments were measured with a 4-mm probe with the rotation rate of 13 kHz, contact time 2 ms
I9F MAS experiments were measured with a 2.5 mm prove with the rotation rate of 30 kHz . For the CP/MAS experiment the contact time was 1 ms.
HPLC
The reactions were routinely monitored with the use of HPLC Agilent 1100 with a UV (PDA) detector equipped with an Ascentis Express CI 8 column (2.7 μτη) (100 x 4,6 mm), at the flow of 1 ml/min, mobile phase A: phosphate buffer (pH ~ 3) and phase B: acetonitrile ( 0 - 2 min 10 % MeCN, 2 - 18 min gradient 10 -> 90 % MeCN). Dynamic vapour sorption (DVS
The dynamic vapour sorption (DVS) patterns were measures with a DVS Advantage 1 device made by the company Surface Measurement Systems. The sample charge in a quartz pot was 20.2 mg and the temperature in the device was 25.4°C. The measurement program used: the sample was loaded with two cycles with the course from the relative humidity of 0% to 90% (sorption) and then from 90% to 0% RH (desorption). This procedure was repeated in the second cycle. As the carrier gas 4.0 N2 was used at the flow rate of 200 seem. Example 1
Preparation of the crystalline Form Z-l
Isopropyl ((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3J4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3- hydroxy-4-memyltetrahydrofuran-2-yl)memoxy)(phenoxy)phosphoryl)-L-alariinate
(SOFOSBUVIR), prepared in accordance with the procedure described in the patent application WO2011123668 in an amount of 1.5 g (2.83 mmol) was dissolved in 8 ml of acetic acid rc-butyl ester (wBuOAc) in a hot state. The clear solution was slowly cooled down to the room temperature and agitated for 3 h. After addition of 20 ml of toluene the white suspension was filtered, the product was washed with toluene (5 ml) and the crystalline Form Z-l was dried in vacuo at the room temperature.
Yield: 1.33 g (87%)
1H NMR (500 MHz, DMSO) δ 11.50 (s, 1H), 7.53 (d, J = 7.0 Hz, 1H), 7.33-7.36 (m, 2H), 7.18-7.21 (m, 2H), 7.117-7.20 (m, 1H), 6.03 (dd, J = 12.7, 10.4 Hz, 1H), 5.83 (d, J= 4.3 Hz, 1H), 5.51 (dd, J= 8.1, 1.6 Hz, 1H), 5.51 (dd, J= 8.1, 1.6 Hz, 1H), 4.85 (hept, J= 6.3 Hz, 1H), 4.33 (dd, J= 11.1, 5.7 Hz, 1H), 4.20 (dt, J= 11.6, 6.0 Hz, 1H), 3.97 (dd, J= 9.1, 4.7 Hz, 1H), 3.85 - 3.76 (m, 1H), 1.25 (d, J= 22.6 Hz, 1H), 1.22 (d, J = 6.8 Hz, 1H), 1.15 (dd, J = 6.3, 0.8 Hz, 1H). 13C NMR (126 MHz, DMSO) δ 172.64 (d, J= 5.1 Hz), 162.78 (s), 150.71 (d, J= 6,3 Hz), 150.47 (s), 129.67 (s), 124.63 (s), 120.09 (d, J = 4.9 Hz), 102.28 (s), 101.04 (s), 99.60 (s), 79.47 (s), 71.51 (s), 68.02 (s), 64.66 (s), 49.79 (s), 26.86 (s), 21.42 (d, J= 4.3 Hz), 19.81 (d, J- 6.5 Hz), 16.56 (d, J = 25.2 Hz).31P NMR (101 MHz, DMSO) δ 3.80 (s). 13C ssNMR (100 MHz,) δ 171.36; 164.12; 151.077; 149.765; 139.370; 123.829; 102.506; 100.263; 88.946; 81.439; 71.358; 68.353; 63.067; 52.396; 21.224; 18.303; 17.781 ppm. iyF ssNMR 5 = -154.66 ppm
HPLC (210 nm): Rt = 9.853 min. Example 2
Preparation of the crystalline Form 2-1
Isopropyl ((S)-(((2R,3R,4R,5R)-5-(254-dioxo-3}4-dihydropyrimidin-l(2H)-yl)-4-iluoro-3- hydroxy-4-memyltetrahydrofuran-2-yl)memoxy)(phenoxy)phosphoryl)-L-alaninate
(SOFOSBUVIR), prepared in accordance with the procedure described in the patent application WO2011123668 in an amount of 0.9 g (1.70 mmol) was dissolved in a mixture of flBuOAc/toluene 10 mL (1:1) in a hot state.
The clear solution was slowly cooled down to the room temperature and agitated for 3 h. After addition of 20 ml of toluene the white suspension was filtered, the product was washed with toluene (5 ml) and the crystalline Form Z-l was dried in vacuo at the room temperature. Yield: 0.73 g (81 %).
1H NMR (500 MHz, DMSO) 6 11.50 (s, lH), 7.53 (d, J = 7.0 Hz, IH), 7.33-7.36 (m, 2H)5 7.18-7.21 (m, 2H), 7.117-7.20 (m, 1H), 6.03 (dd, J= 12.7, 10.4 Hz, 1H), 5.83 (d, .7= 4.3 Hz, 1H), 5.51 (dd, J= 8.1, 1.6 Hz, 1H), 5.51 (dd, J= 8.1, 1.6 Hz, 1H), 4.85 (hept, J= 6.3 Hz, 1H), 4.33 (dd, J= 11.1, 5.7 Hz, 1H), 4.20 (dt, J = 11.6, 6.0 Hz, 1H), 3.97 (dd, J= 9.1, 4.7 Hz, 1H), 3.85 - 3.76 (m, 1H), 1.25 (d, J= 22.6 Hz, 1H), 1.22 (d, J= 6.8 Hz, 1H), 1.15 (dd, J= 6.3, 0.8 Hz, 1H). I3C NMR (126 MHz, DMSO) δ 172.64 (d, J= 5.1 Hz), 162.78 (s), 150.71 (d, J= 6,3 Hz), 150.47 (s), 129.67 (s), 124.63 (s), 120.09 (d, J = 4.9 Hz), 102.28 (s), 101.04 (s), 99.60 (s), 79.47 (s), 71.51 (s), 68.02 (s), 64.66 (s), 49.79 (s), 26.86 (s), 21.42 (d, J = 4.3 Hz), 19.81 (d, J= 6.5 Hz), 16.56 (d, J = 25.2 Hz).3IP NMR (101 MHz, DMSO) δ 3.80 (s). 13C ssNMR (100 MHz,) δ 171.36; 164.12; 151.077; 149.765; 139.370; 123.829; 102.506; 100.263; 88.946; 81.439; 71.358; 68.353; 63.067; 52.396; 21.224; 18.303; 17.781 ppm. I9F ssNMR δ - 154.66 ppm HPLC (210 nm): Rx = 9.853 min.

Claims

Claims:
1. The crystalline form Z-1 of sofosbuvir Z-1, characterized by the following diffraction peaks 8.0; 12.3; 17.1; 19.9 and 20.8 ±0,2° 2-theta with the use of CuKoc radiation.
2. The crystalline form in accordance with claim 1, which is further characterized by the following diffraction peaks: 10.3; 13.4; 16.1; 17.9; 19.3; 23.6; 24.8 and 27.0 ± 0.2° 2- theta.
3. The crystalline form Z- 1 of Sofosbuvir, characterized by FTIR spectra with the bands 3251, 1719, 1669, 1265, 1092 and 945 ± 4 cm-1.
4. The crystalline form Z-1 of Sofosbuvir, characterized by the FT-Raman spectrum with the following maximum values: 2987, 1718, 1671, 1373, 1217, 1007, 774 ± 4 cm"1.
5. The crystalline form Z-1 of Sofosbuvir, characterized by 19 F ss NMR spectra,
exhibiting a single band corresponding to the chemical shift δ - 154.66 ppm.
6. A method for the production of the crystalline form Z-1 of SOFOSBUVIR in
accordance with any of the previous claims, characterized by crystallization from a solvent or a solvent mixture of an ester of a C3 to C5 alcohol and a CI to C4 acid.
7. The method in accordance with claim 6, characterized in that said ester is an ester with the total number of 5 to 8 carbon atoms.
8. The method in accordance with claims 6 or 7, characterized in that the crystallization is carried out from a solvent or a solvent mixture containing n-butyl acetate.
9. The method in accordance with claims 6 to 8, characterized in that the method is carried out from pure nBuOAc.
10. The method in accordance with claims 6 to 8, characterized in that the method is carried out from a mixture of nBuOAc and a co-solvent.
11. The method in accordance with claim 10 where the co-solvent is toluene.
12. The method in accordance with claim 10 where the co-solvent is hexane.
13. The method in accordance with claim 10 where the co-solvent is DCM.
PCT/CZ2015/000078 2014-07-17 2015-07-17 A new form of sofosbuvir and a method of its preparation WO2016008461A1 (en)

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Cited By (10)

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Publication number Priority date Publication date Assignee Title
US10214553B2 (en) 2014-06-13 2019-02-26 Teva Pharmaceuticals International Gmbh Solid state forms of sofosbuvir
EP3174889B1 (en) * 2014-08-01 2019-11-20 HC-Pharma AG Sofosbuvir in crystalline form and process for its preparation
US10738071B2 (en) 2016-03-17 2020-08-11 Mylan Laboratories Limited Polymorphic forms of sofosbuvir
RU2656228C1 (en) * 2017-06-13 2018-06-04 Олег Ростиславович Михайлов WEAKLY CRYSTALLISED β-MODIFICATION OF (S)-ISOPROPYL 2-((S)-(((2R,3R,4R,5R)-5-(2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-(2H)-YL)-4-FLUORO-3-HYDROXY-4-METHYLTETRAHYDROFURAN-2-YL)METHOXY)-(PHENOXY)PHOSPHORYLAMINO)PROPANOATE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON
RU2656228C9 (en) * 2017-06-13 2019-04-16 Олег Ростиславович Михайлов WEAKLY CRYSTALLISED β-MODIFICATION OF (S)-ISOPROPYL 2-((S)-(((2R,3R,4R,5R)-5-(2,4-DIOXO-3,4-DIHYDROPYRIMIDIN-(2H)-YL)-4-FLUORO-3-HYDROXY-4-METHYLTETRAHYDROFURAN-2-YL)METHOXY)-(PHENOXY)PHOSPHORYLAMINO)PROPANOATE, METHOD FOR PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITION BASED THEREON
WO2019025600A1 (en) 2017-08-03 2019-02-07 Sandoz Ag Sofosbuvir hydrate
CN109517018B (en) * 2018-12-29 2021-05-04 石药集团中奇制药技术（石家庄）有限公司 New crystal form of Sofosbuvir and preparation method thereof
CN111072742A (en) * 2019-12-23 2020-04-28 南京正大天晴制药有限公司 Novel crystal form of medicine for treating hepatitis C and composition thereof
CN111072742B (en) * 2019-12-23 2022-12-02 南京正大天晴制药有限公司 Novel crystal form of medicine for treating hepatitis C and composition thereof
WO2021203409A1 (en) * 2020-04-10 2021-10-14 南京正大天晴制药有限公司 Novel non-hygroscopic low-variability crystalline form for treatment of hepatitis c

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