CN104277088A - Sofosbuvir monocrystal M and preparation method and applications of sofosbuvir monocrystal M - Google Patents

Sofosbuvir monocrystal M and preparation method and applications of sofosbuvir monocrystal M Download PDF

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Publication number
CN104277088A
CN104277088A CN201410591710.6A CN201410591710A CN104277088A CN 104277088 A CN104277088 A CN 104277088A CN 201410591710 A CN201410591710 A CN 201410591710A CN 104277088 A CN104277088 A CN 104277088A
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suo feibuwei
monocrystalline
alkyl
crystal
sofosbuvir
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汤律进
周守明
王彩琴
冯汝宏
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汤律进
周守明
王彩琴
冯汝宏
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06Pyrimidine radicals
    • C07H19/10Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07HSUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00Processes for the preparation of sugar derivatives
    • C07H1/06Separation; Purification
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Abstract

The invention discloses a sofosbuvir monocrystal M and a preparation method and applications of the sofosbuvir monocrystal M. The sofosbuvir monocrystal prepared according to the preparation method disclosed by the invention belongs to a monoclinic system, and the space group is P21; the unit cell parameters are as follows: a=13.816 (3) A, b=5.973 (2) A, c=17.666 (4) A, and Beta=108.96 (3); the unit cell volume is 1378.7 (3) A3, and the number Z of molecules in a unit cell is 2. Solvents selected in the sofosbuvir monocrystal M disclosed by the invention are methylene chloride, chloroform, ethanol, isopropanol, acetonitrile, and C3-C7 alkyl cyanoacetate or C3-C7 dialkyl carbonate or C3-C7 dialkyl oxalate, and the like, and the sofosbuvir monocrystal is prepared by using a solvent evaporation method. The sofosbuvir monocrystal prepared according to the preparation method disclosed by the invention has good stability.

Description

Suo Feibuwei monocrystalline M and its production and use
Technical field
The present invention relates to a kind of Suo Feibuwei monocrystalline M and its production and use.
Background technology
The hepatitis C medicine Suo Feibuwei (trade(brand)name: Sovaldi of lucky Leadd B.V, popular name: Sofosbuvir, GS-7977 by name before, PSI-7977,400mg tablet) obtain U.S. food Drug Administration (FDA) approval on December 6th, 2013 for gene 1 type, 2 types, the treatment of 3 types and 4 type chronic hepatitis Cs (Hepatitis C) adult patient.Suo Feibuwei is the first granted medicine that can be used for the full oral treatment regimes of hepatitis C, when treating for specific gene type (2 types, 3 types) chronic hepatitis C, can eliminate the demand to conventional injection interfering effects of drug element (IFN).
Suo Feibuwei (Sofosbuvir) is hepatitis C virus NS 5 B AG14361, HCV genotype 2 (HCV GT2), HCV genotype 3 (HCV GT3) are infected, Suo Feibuwei only need with ribavirin (Ribavirin) coupling, the whole world that therefore it become for treating hepatitis c is first without the need to using the full oral combination therapy of Interferon, rabbit simultaneously.FDA also ratifies the infection that Suo Feibuwei combines Peg-IFN alpha-2b (peg-interferon alfa), ribavirin (Ribavirin) is used for the treatment of genotype 1 and 4 (HCV GT1, HCV GT4) simultaneously.
The crystal formation research of medicine and solid-state to be characterized in pharmaceutical industry significant, because the aggregate that the Various Complex that formed by weak interaction of drug molecule is orderly, the difference of its three-dimensional arrangement will cause the change of physical and chemical properties of drugs.The different crystal forms of same medicine often has different biochemical properties, and in stability, solubleness etc., there were significant differences.In addition, because the crystalline form of medicine has great effect to the absorption of medicine, transhipment, thus change the bioavailability of medicine, considerable influence can be produced to curative effect.
It is not only relevant with the chemical structure of drug molecule that the crystal formation of medicine belongs to which kind of crystallographic system, which kind of lattice structure, also with during preparation crystallization cools when solvent for use kind, strength of solution, crystallization simultaneously, the factor such as velocity of evaporation, drying means is closely related.The research of polymorph in pharmaceuticals has epochmaking effect to the stability ensured in pharmaceutical production storage process and the safety and effectiveness in Clinical practice, and in addition, the design of crystalline form to formulation of medicine also plays a key role.The research of drug crystal forms and solid-state sign, at American-European pharmaceutical industry comparative maturity, also draws attention gradually in China.
In patent of invention WO2010135569, WO2011123645, CN102459299A, Gillette moral once disclosed and protected three kinds of monocrystalline and six kinds of crystal formations and preparation method thereof of Suo Feibuwei.The present invention adopts different crystallization method, has obtained the novel monocrystalline of Suo Feibuwei, and six kinds of crystal formations of the Suo Feibuwei that its crystal formation and aforementioned Gillette moral patent are protected are neither same.
Summary of the invention
Suo Feibuwei monocrystalline M that the object of the present invention is to provide a kind of crystal formation brand-new and its production and use, the present invention not only tests its crystalline structure, also characterizes its performance.
Technical solution of the present invention is:
A kind of Suo Feibuwei monocrystalline M, it is characterized in that: its Advances in crystal X-ray diffraction figure has following feature, and crystal belongs to oblique system, spacer is P21, unit cell parameters: β=108.96 (3) °.Unit cell volume molecule number Z=2 in structure cell.
The medicine used in the present invention is Suo Feibuwei; chemical name is S-2-(((S)-(((2R; 3R; 4R; 5R)-5-(2; 4-oxo-3,4-dihydro-pyrimidin-1 (2H)-Ji)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran (THF)-2-base) methoxyl group) (phenoxy group) phosphoryl) amino) isopropyl propionate, molecular formula is C 22h 29fN 3o 9p.
Described Suo Feibuwei monocrystalline M, its powder x-ray diffraction figure has characteristic diffraction angles 2 θ, spacing d and relative intensity %, and 2 θ errors are 0.2.
A preparation method of Suo Feibuwei monocrystalline M, is characterized in that: be dissolved in by Suo Feibuwei in organic solvent, and solvent temperature, in the scope of 30-80 DEG C, naturally cools to room temperature after dissolving, adds or does not add dissolved agent, and cooling crystallize out, filters and get final product.
The consumption of described Suo Feibuwei medicine and the weightmeasurement ratio of consumption of organic solvent are 1g: 1 ~ 50ml.
Described organic solvent is methylene dichloride, chloroform, ethanol, Virahol, acetonitrile, the alkyl cyanide acetic ester of C3-C7, the alkyl carbonate of two C3-C7 or two C3-C7 alkyl barkite.
Described dissolved agent is be selected from a kind of or two or more arbitrarily combination in water, methylene dichloride, chloroform, acetonitrile, the alkyl carbonate of two C3-C7, two C3-C7 alkyl barkite, the alkyl malonic ester of two C3-C7, the alkyl cyanide acetic ester of C3-C7, Virahol, the trimethyl carbinol, tetrahydrofuran (THF), methyl tertiary butyl ether, and dissolved agent is different from described organic solvent.
The consumption of described dissolved agent and the volume ratio of solvent load are 0 ~ 20: 1.
A kind of pharmaceutical composition, comprises the described Suo Feibuwei monocrystalline M of one or more pharmaceutically acceptable carriers and significant quantity.
The application of a kind of described Suo Feibuwei monocrystalline M in the anti-chronic hepatitis C medicine of preparation.
Rigaku MicroMax 002+ single crystal diffractometer is adopted to collect diffracted intensity data, CuK α radiation, focusing monochromator altogether, collimator tube diameter phi=0.30mm, crystal and ccd detector distance d=45mm, pipe pressure 45kv, pipe stream 0.88mA, w and k scan mode, observable point is 3478, and data integrity degree is 96.5%.
Use direct method (Shelx97) to resolve crystalline structure on computers, obtain 36 non-hydrogen atom positions from E figure, use least-squares refinement structural parameter and differentiate atomic species, finally determining that asymmetry unit molecular formula is C 22h 29n 3o 9fP, molecular weight is 529.46, calculates crystalline density 1.275g/cm 3.Under crystalline state, molecular arrangement belongs to the first spacer, therefore sample should have optically active.The Flack coefficient of crystalline structure is 0.03 (3) as calculated, obtains molecule absolute configuration.
Compound calculated powder X diffraction peak table
The preparation method of Suo Feibuwei medicine monocrystalline of the present invention can be heating-room temperature volatilization method, and concrete steps are as follows:
(1) by Suo Feibuwei and organic solvent in certain ratio mixing, be placed in container and stir lower heating;
(2) backflow stops after within 30-60 minute, making the complete CL of Suo Feibuwei stirring and heating;
(3) filtered by Suo Feibuwei solution, filtrate is volatilized under being placed in room temperature crystallization.
Organic solvent used in the present invention has chloroform, ethanol, Virahol, acetonitrile, water, two C 3-C 7alkyl carbonate (ROCOOR ') or two C 3-C 7alkyl barkite (ROCOCOOR ') etc., the temperature of heating for dissolving Suo Feibuwei is at 20-80 DEG C.
Bian method provided by the present invention prepares Suo Feibuwei crystal formation, carries out stability study.Under accelerated stability condition, (temperature 40 ± 20 DEG C) places 6 months, respectively at the 0th month, January, February, March, April, May, June carries out Liquid Detection, sample still keeps stable after six months, and content is more than 99.6%.
Suo Feibuwei new crystal obtained by the present invention has extraordinary application prospect in the process for the treatment of hepatitis c virus infection.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the invention will be further described.
Fig. 1 is molecule structure cell accumulation graph of the present invention.
Fig. 2 is monocrystalline molecule stereo structure sciagraph.
This compound molecule skeleton has 1 five yuan furanose ring A (envelope type), and 1 hexa-atomic pyrimidine ring B (plane formula) and 1 phenyl ring C form.Between ring, least square interfacial angle is: A/B:95.9 °, B/C:102.7 °, A/C:18.4 °.
Fig. 3 is calculated powder diffracting spectrum.
Embodiment
The present invention is further illustrated below, but do not limited the present invention in any form, and any conversion done based on training centre of the present invention or replacement, all belong to protection scope of the present invention.
The preparation of embodiment 1: Suo Feibuwei monocrystalline
1g Suo Feibuwei is dissolved in chloroform-isopropanol (volume ratio 50:1) mixing solutions of 20mL 50 DEG C, stirring and dissolving, then the solution being dissolved with Suo Feibuwei is cooled to room temperature, stirring and crystallizing simultaneously, filter to no longer including after solid is separated out, with a small amount of cold solvent (hexane or methylene dichloride) (4 DEG C) washing, sample presentation is made single crystal X diffraction and is measured crystalline structure.Adopt HPLC to detect the Suo Feibuwei obtained, content is 99.9%; Adopt gas chromatographic detection, residual solvent levels is lower than 40ppm.
Its Advances in crystal X-ray diffraction figure has following feature, and crystal belongs to oblique system, and spacer is P21, unit cell parameters: β=108.96 (3) °.Unit cell volume molecule number Z=2 in structure cell.
The medicine used in the present invention is Suo Feibuwei; chemical name is S-2-(((S)-(((2R; 3R; 4R; 5R)-5-(2; 4-oxo-3,4-dihydro-pyrimidin-1 (2H)-Ji)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran (THF)-2-base) methoxyl group) (phenoxy group) phosphoryl) amino) isopropyl propionate, molecular formula is C 22h 29fN 3o 9p.
Described Suo Feibuwei monocrystalline M, its powder x-ray diffraction figure has characteristic diffraction angles 2 θ, spacing d and relative intensity %, and 2 θ errors are 0.2.
The preparation of embodiment 2: Suo Feibuwei monocrystalline
1g Suo Feibuwei is dissolved in the methylcarbonate of 6mL 50 DEG C, slowly crystallization under stirring, collecting by filtration crystal, washs with a small amount of cold solvent (hexane or methylene dichloride), choose crystal sample presentation and measure single crystal X diffraction, determine the three-dimensional arrangement of obtained Suo Feibuwei new crystal.
Its Advances in crystal X-ray diffraction figure has following feature, and crystal belongs to oblique system, and spacer is P21, unit cell parameters: β=108.96 (3) °.Unit cell volume molecule number Z=2 in structure cell.
The medicine used in the present invention is Suo Feibuwei; chemical name is S-2-(((S)-(((2R; 3R; 4R; 5R)-5-(2; 4-oxo-3,4-dihydro-pyrimidin-1 (2H)-Ji)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran (THF)-2-base) methoxyl group) (phenoxy group) phosphoryl) amino) isopropyl propionate, molecular formula is C 22h 29fN 3o 9p.
The preparation of embodiment 3: Suo Feibuwei new crystal
1g Suo Feibuwei is dissolved in the 10mL oxalic acid diethyl ester of 50 DEG C, slowly cools to room temperature, volatilization crystallization.Solid to be no longer included is separated out, collecting by filtration crystal, and with a small amount of cold solvent (hexane or methylene dichloride) washing, sample presentation measures single crystal X diffraction subsequently.
Its Advances in crystal X-ray diffraction figure has following feature, and crystal belongs to oblique system, and spacer is P21, unit cell parameters: β=108.96 (3) °.Unit cell volume molecule number Z=2 in structure cell.
The medicine used in the present invention is Suo Feibuwei; chemical name is S-2-(((S)-(((2R; 3R; 4R; 5R)-5-(2; 4-oxo-3,4-dihydro-pyrimidin-1 (2H)-Ji)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran (THF)-2-base) methoxyl group) (phenoxy group) phosphoryl) amino) isopropyl propionate, molecular formula is C 22h 29fN 3o 9p.
Embodiment 4:
A preparation method of Suo Feibuwei monocrystalline M, is dissolved in Suo Feibuwei in organic solvent, and solvent temperature, in the scope of 30-80 DEG C, naturally cools to room temperature after dissolving, adds (or not adding) dissolved agent, and cooling crystallize out, filters and get final product.
The consumption of described Suo Feibuwei medicine and the weightmeasurement ratio of consumption of organic solvent are 1g:1 ~ 50ml.
Described organic solvent is methylene dichloride, chloroform, ethanol, Virahol, acetonitrile, the alkyl cyanide acetic ester of C3-C7, the alkyl carbonate of two C3-C7 or two C3-C7 alkyl barkite.
Described dissolved agent is be selected from a kind of or two or more arbitrarily combination in water, methylene dichloride, chloroform, acetonitrile, the alkyl carbonate of two C3-C7, two C3-C7 alkyl barkite, the alkyl malonic ester of two C3-C7, the alkyl cyanide acetic ester of C3-C7, Virahol, the trimethyl carbinol, tetrahydrofuran (THF), methyl tertiary butyl ether, and dissolved agent is different from described organic solvent.
The consumption of described dissolved agent and the volume ratio of solvent load are 0 ~ 20: 1.
The Suo Feibuwei monocrystalline M obtained, its Advances in crystal X-ray diffraction figure has following feature, and crystal belongs to oblique system, and spacer is P21, unit cell parameters: β=108.96 (3) °.Unit cell volume molecule number Z=2 in structure cell.Its powder x-ray diffraction figure has characteristic diffraction angles 2 θ, spacing d and relative intensity %, and 2 θ errors are 0.2.
The medicine used in the present invention is Suo Feibuwei; chemical name is S-2-(((S)-(((2R; 3R; 4R; 5R)-5-(2; 4-oxo-3,4-dihydro-pyrimidin-1 (2H)-Ji)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran (THF)-2-base) methoxyl group) (phenoxy group) phosphoryl) amino) isopropyl propionate, molecular formula is C 22h 29fN 3o 9p.
A kind of pharmaceutical composition, comprises the described Suo Feibuwei monocrystalline M of one or more pharmaceutically acceptable carriers and significant quantity.
The application of a kind of described Suo Feibuwei monocrystalline M in the anti-chronic hepatitis C medicine of preparation.
Rigaku MicroMax 002+ single crystal diffractometer is adopted to collect diffracted intensity data, CuK αradiation, altogether focusing monochromator, collimator tube diameter phi=0.30mm, crystal and ccd detector distance d=45mm, pipe pressure 45kv, pipe stream 0.88mA, w and k scan mode, observable point is 3478, and data integrity degree is 96.5%.
Use direct method (Shelx97) to resolve crystalline structure on computers, obtain 36 non-hydrogen atom positions from E figure, use least-squares refinement structural parameter and differentiate atomic species, finally determining that asymmetry unit molecular formula is C 22h 29n 3o 9fP, molecular weight is 529.46, calculates crystalline density 1.275g/cm 3.Under crystalline state, molecular arrangement belongs to the first spacer, therefore sample should have optically active.The Flack coefficient of crystalline structure is 0.03 (3) as calculated, obtains molecule absolute configuration.

Claims (9)

1. Yi Zhong Suo Feibuwei monocrystalline M, it is characterized in that: its Advances in crystal X-ray diffraction figure has following feature, crystal belongs to oblique system, spacer is P21, unit cell parameters: a=13.816 (3), b=5.973 (2), c=17.666 (4), β=108.96 (3) o.Unit cell volume V=1378.5 (5), molecule number Z=2 in structure cell.
2. Suo Feibuwei monocrystalline M according to claim 1, it is characterized in that: its powder x-ray diffraction figure has characteristic diffraction angles 2 θ, spacing d and relative intensity %, 2 θ errors are 0.2.
3. a preparation method of Suo Feibuwei monocrystalline M as claimed in claim 1, is characterized in that: be dissolved in by Suo Feibuwei in organic solvent, and solvent temperature is in the scope of 30-80 DEG C, room temperature is naturally cooled to after dissolving, add or do not add dissolved agent, cooling crystallize out, filters and get final product.
4. the preparation method of Suo Feibuwei monocrystalline M according to claim 3, is characterized in that: the consumption of described Suo Feibuwei medicine and the weightmeasurement ratio of consumption of organic solvent are 1g: 1 ~ 50ml.
5. the preparation method of the Suo Feibuwei monocrystalline M according to claim 3 or 4, is characterized in that: described organic solvent is methylene dichloride, chloroform, ethanol, Virahol, acetonitrile, the alkyl cyanide acetic ester of C3-C7, the alkyl carbonate of two C3-C7 or two C3-C7 alkyl barkite.
6. the preparation method of the Suo Feibuwei new crystal according to claim 3 or 4, it is characterized in that: described dissolved agent is be selected from a kind of or two or more arbitrarily combination in water, methylene dichloride, chloroform, acetonitrile, the alkyl carbonate of two C3-C7, two C3-C7 alkyl barkite, the alkyl malonic ester of two C3-C7, the alkyl cyanide acetic ester of C3-C7, Virahol, the trimethyl carbinol, tetrahydrofuran (THF), methyl tertiary butyl ether, and dissolved agent is different from described organic solvent.
7. the preparation method of the Suo Feibuwei new crystal according to claim 3 or 4, is characterized in that: the consumption of described dissolved agent and the volume ratio of solvent load are 0 ~ 20: 1.
8. a pharmaceutical composition, comprises the described Suo Feibuwei monocrystalline M of one or more pharmaceutically acceptable carriers and significant quantity.
9. the application of Suo Feibuwei monocrystalline M according to claim 1 in the anti-chronic hepatitis C medicine of preparation.
CN201410591710.6A 2014-10-29 2014-10-29 Sofosbuvir monocrystal M and preparation method and applications of sofosbuvir monocrystal M Pending CN104277088A (en)

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CN104829673A (en) * 2015-03-12 2015-08-12 南京旗昌医药科技有限公司 Preparation method of sofosbuvir crystal form 6
CN105017359A (en) * 2015-07-08 2015-11-04 苏州晶云药物科技有限公司 Preparation method of Sofosbuvir crystal form
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WO2017029408A1 (en) * 2015-08-20 2017-02-23 Ratiopharm Gmbh Solid state forms of sofosbuvir
CN108084237A (en) * 2016-11-23 2018-05-29 广东东阳光药业有限公司 Monohydrate of Suo Feibuwei and preparation method thereof
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CN106146589A (en) * 2015-04-10 2016-11-23 正大天晴药业集团股份有限公司 The crystallization of deuterated nucleoside derivates
CN105017359A (en) * 2015-07-08 2015-11-04 苏州晶云药物科技有限公司 Preparation method of Sofosbuvir crystal form
WO2017029408A1 (en) * 2015-08-20 2017-02-23 Ratiopharm Gmbh Solid state forms of sofosbuvir
CN108084237A (en) * 2016-11-23 2018-05-29 广东东阳光药业有限公司 Monohydrate of Suo Feibuwei and preparation method thereof
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
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