CN108659077A - The crystal form and preparation method, purposes, derivative composition of nucleoside phosphoramidite class compound - Google Patents
The crystal form and preparation method, purposes, derivative composition of nucleoside phosphoramidite class compound Download PDFInfo
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- 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
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Abstract
The invention belongs to medicinal chemistry arts, and in particular to the crystal form and preparation method, purposes, derivative composition of nucleoside phosphoramidite class compound.The technical problem to be solved by the present invention is to the drug side-effect of existing treatment hepatitis C is more, dosage regimen is complicated, and drug resistance easily occurs, and the kidney burden of making patients is more toxic liver cell, and only effective to certain genotype.The scheme that invention solves above-mentioned technical problem is to provide a kind of crystal form A and B of nucleoside phosphoramidite class compound and is characterized by the peak of the XRPD collection of illustrative plates angle of diffraction (2 θ), not only it can be taken orally, it is combined also without Ribavirin is combined with Peg-IFN alpha-2b, and it is effective to all genotype, there is good application prospect and market value.
Description
Technical field
The invention belongs to medicinal chemistry arts, and in particular to the crystal form and preparation method of nucleoside phosphoramidite class compound, spread out at purposes
Raw composition.
Background technology
Hepatitis C Virus (HCV) is a kind of single-stranded, positive chain RNA virus, belongs to hepatitis virus category flaviviridae.According to volume
The gene of code NS5B ribonucleic acid dependent form ribonucleic acid polymerases is different, and Hepatitis C Virus is divided into 6 genotype, 50 Asias
Type.Distribution of the different genotype in the whole world is different.
Hepatitis C infection is worldwide Major health problems.According to the statistics of the World Health Organization, the whole world there are about
200000000 people infect hepatitis, annual new infections person three, 4,000,000.After infection, 20% the infected can remove virus automatically, but big
Part the infected can carry virus throughout one's life.The chronic liver diseases such as hepatic sclerosis, liver cancer can be developed into 10%~20% the infected.Third
The main reason for liver function decompensation caused by type hepatitis is all worldwide liver transplant, brings to patient and society
Heavy financial burden.
In known technology, the therapeutic scheme of standard is Peg-IFN alpha-2b joint Ribavirin.However the therapy is only
It is effective to 40%~50% 1 patient of genotype and 75% genotype 2,3 patients.To certain sub- crowds, polyethylene glycol interference
The effect of element joint Ribavirin, is bad.Therefore, first generation hcv protease inhibitors telavi and Bo Xipu
Wei Xiangji emerges.Both drugs are combined with Peg-IFN alpha-2b/Ribavirin, can improve the virus of 1 type patient of gene
Clearance rate shortens the course for the treatment of.But this three new combination treatments bring new problem, such as more side effects, give prescription
Case is complicated, drug resistance easily occurs, and only effective to the patient of 1 virus of infection genotype.
NS5B ribonucleic acid dependent form ribonucleic acid polymerases are a kind of important antiviral molecule target spots.This virus is special
Anisotropic enzyme is most important to the duplication of Hepatitis C Virus.
Suo Feibuwei (sofosbuvir) is a kind of Hepatitis C Virus (HCV) nucleotide analog NS5B polymerases inhibition
Agent, it is suitable for as the composition in combination antiviral therapy scheme, being infected to treat chronic hepatitis C (CHC).But rope
Fei Buwei and its metabolite are mainly removed by kidney, for the patient of serious kidney injury, can aggravate its kidney burden.And
And the prodrug based on Suo Feibuwei change structure compound metabolic mechanism it is identical as Suo Feibuwei, there is also similar to Suo Feibuwei
Defect.In addition, Suo Feibuwei is poor to the drug effect of 3 the infected of genotype, the course for the treatment of 24 weeks.And genotype 1,2 and 4 is infected
The course for the treatment of of person needs 12 weeks.
The drug side-effect of existing treatment hepatitis C is more, and dosage regimen is complicated, and drug resistance, the kidney of making patients easily occurs
Burden, is more toxic liver cell, and only effective to certain genotype, present inventor is untiringly studied, as a result
Be found that it is a kind of be metabolized in hepatic tissue after nucleosides more than the nucleoside triphosphate that generates of the nucleoside triphosphate peso Fei Buwei that generates
The new compound of phosphoramide types and its related crystal form, as the inhibitor of Hepatitis C Virus (HCV) NS5B polymerases,
Its drug effect peso Fei Buwei medicines are good, to the toxicity smaller of liver cell.
Invention content
The object of the present invention is to provide a kind of crystal form of nucleoside phosphoramidite class compound and preparation method, purposes, derivative compositions.
The nucleoside phosphoramidite class compound, hereinafter referred to as type I compound, structure are as follows：
Compound of formula I and its preparation and use be recorded in applicant submission application No. is the China of 201510632656.X
In patent application.Above-mentioned Chinese patent application quotes addition herein with its entirety.
The crystal form of compound of formula I provided by the present invention not only shows extremely low toxicity and excellent pharmacokinetics
Matter also has the very favorable property of one or more of.For example, the advantages of crystal form of the present invention include but not limited to compared with
High solubility, preferable pharmacokinetic properties and good stability, is suitble to prepare pharmaceutical preparation, and the crystal form
Preparation method is simple and effective, is easy to amplification production.
Specifically, the advantageous property of crystal form of the invention comprising but it is not limited to solubility, dissolution rate, light shine, low
Hygroscopicity, heat-resisting quantity, resistance to height be moist, mobility and the viscous stickiness etc. being obviously improved.For example, the crystal form of the present invention is in preparation mistake
It can obviously reduce filtration time in journey, shorten the production cycle, it is cost-effective.The crystal form of the present invention has good photostability,
It can guarantee reliability of the crystal form in storage and transport, to ensure the safety of preparation, and the crystal form does not need
It to prevent from being illuminated by the light influences that extra package is taken to handle, to reduce cost.The crystal form will not be generated because of illumination effect
Degradation, the safety for improving preparation and the validity after long-term storage.The patient for taking the crystal form will not worry preparation because
It is exposed under daylight and generates photosensitized reaction.
The crystal form of the present invention is few when storing or transport at ambient temperature or less degradation, and the crystal form is in differential scanning
Melting or desolvation when more than 50 DEG C are shown in calorimetric (DSC) analysis, and there is preferable thermal stability, it can be steady for a long time
It is fixed to keep, and suitable for the formulation manufacturing processes of standard.
The crystal form of the present invention is easily prepared and is particularly suited for the preparation of preparation.For example, the crystal form of the present invention is milled
At fine powder, it is sieved with 500 μm and 250 μm of screens.It mills after sieving and the X-ray powder diffraction peak of crystal form and to mill sieving
It is preceding consistent.
The crystal form of the present invention has the effect of excellent in the treatment of Hepatitis C Virus, can keep enough biology work
Property, the dose therapeutically effective of the compound of Formulas I can be provided in vivo.
The crystal form of the present invention is suitble to and is prepared convenient for a large amount of, and the preparation being prepared with above-mentioned crystal form can reduce irritation simultaneously
It improves and absorbs so that in terms of accretion rate the problem of is addressed, and toxicity is remarkably reduced, and safety is improved, effectively
Ground ensure that the quality and efficiency of preparation.
Specifically, An embodiment provides the crystal form A of above-mentioned compound of formula I, the feature 2 of powder diffraction
The angles θ be included in 3.10 ± 0.2 °, 6.78 ± 0.2 °, 10.43 ± 0.2 °, 11.32 ± 0.2 °, 12.58 ± 0.2 °, 13.72 ±
0.2 °, 17.27 ± 0.2 °, the characteristic peak at 18.28 ± 0.2 ° of the angle of diffraction (2 θ).
In preferred embodiments, 2 angles θ of feature of the crystal form A of the compound of formula I, powder diffraction are included in
3.10±0.2°、6.78±0.2°、10.43±0.2°、11.32±0.2°、11.79±0.2°、12.58±0.2°、13.72±
0.2°、15.50±0.2°、17.27±0.2°、17.67±0.2°、18.28±0.2°、23.07±0.2°、23.51±0.2°
The angle of diffraction (2 θ) at characteristic peak.
In a more preferred embodiment, 2 angles θ of feature of the crystal form A of the compound of formula I, powder diffraction are included in
3.10±0.2°、6.78±0.2°、10.43±0.2°、11.32±0.2°、11.79±0.2°、12.58±0.2°、13.72±
0.2°、14.68±0.2°、15.50±0.2°、17.27±0.2°、17.67±0.2°、18.28±0.2°、19.44±0.2°、
20.94±0.2°、23.07±0.2°、23.51±0.2°、25.13±0.2°、25.90±0.2°、26.64±0.2°、26.87
Characteristic peak at ± 0.2 ° and 28.38 ± 0.2 ° of the angle of diffraction (2 θ).
In particularly preferred embodiments, the XRPD collection of illustrative plates of the crystal form A of the compound of the Formulas I include with shown in Fig. 1
Peak at the substantially the same angle of diffraction (2 θ).
In particularly preferred embodiments, basic shown in the XRPD peak positions of the crystal form A of the compound of the Formulas I and Fig. 1
It is upper identical.
In preferred embodiments, the DSC collection of illustrative plates of the crystal form A of the compound of Formulas I of the invention is included in about 126.93
Characteristic peak at DEG C.
In a more preferred embodiment, the DSC collection of illustrative plates of the crystal form A of the compound of the Formulas I include with it is basic shown in Fig. 2
Characteristic peak at upper identical temperature.
In particularly preferred embodiments, the feature peak position and Fig. 2 of the DSC collection of illustrative plates of the crystal form A of the compound of the Formulas I
It is shown substantially the same.
An alternative embodiment of the invention provides the crystal form B of compound of formula I, and 2 angles θ of feature of powder diffraction are included in
3.10±0.2°、6.75±0.2°、9.01±0.2°、10.10±0.2°、11.06±0.2°、11.81±0.2°、14.17±
0.2°、15.05±0.2°、15.84±0.2°、16.93±0.2°、18.14±0.2°、18.78±0.2°、20.30±0.2°
With the characteristic peak at 20.80 ± 0.2 ° of the angle of diffraction (2 θ).
In preferred embodiments, 2 angles θ of feature of the crystal form B of the compound of formula I, powder diffraction are included in
3.10±0.2°、6.75±0.2°、9.01±0.2°、10.10±0.2°、11.06±0.2°、11.81±0.2°、12.03±
0.2°、12.84±0.2°、14.17±0.2°、15.05±0.2°、15.57±0.2°、15.84±0.2°、16.93±0.2°、
17.44±0.2°、18.14±0.2°、18.78±0.2°、20.30±0.2°、20.80±0.2°、21.78±0.2°、22.44
Characteristic peak at ± 0.2 ° and 23.11 ± 0.2 ° of the angle of diffraction (2 θ).
In a more preferred embodiment, 2 angles θ of feature of the crystal form B of the compound of formula I, powder diffraction are included in
3.10±0.2°、6.75±0.2°、9.01±0.2°、10.10±0.2°、11.06±0.2°、11.81±0.2°、12.03±
0.2°、12.84±0.2°、14.17±0.2°、15.05±0.2°、15.57±0.2°、15.84±0.2°、16.93±0.2°、
17.44±0.2°、18.14±0.2°、18.78±0.2°、19.28±0.2°、20.30±0.2°、20.80±0.2°、21.78
±0.2°、22.26±0.2°、22.44±0.2°、23.11±0.2°、23.55±0.2°、24.86±0.2°、26.17±
0.2 °, 27.27 ± 0.2 °, 27.78 ± 0.2 °, 30.62 ± 0.2 °, 31.02 ± 0.2 °, 31.40 ± 0.2 ° and 34.34 ± 0.2 °
The angle of diffraction (2 θ) at characteristic peak.
In particularly preferred embodiments, the XRPD collection of illustrative plates of the crystal form B of the compound of the Formulas I includes as shown in figure 3
Peak at the substantially the same angle of diffraction (2 θ).
In particularly preferred embodiments, the XRPD peak positions of the crystal form B of the compound of the Formulas I are basic as shown in figure 3
It is upper identical.
In preferred embodiments, the DSC collection of illustrative plates of the crystal form B of the compound of Formulas I of the invention is included in about 141.3 DEG C
The characteristic peak at place.
In a more preferred embodiment, the DSC collection of illustrative plates of the crystal form B of the compound of the Formulas I include with it is basic shown in Fig. 4
Characteristic peak at upper identical temperature.
In particularly preferred embodiments, the feature peak position and Fig. 4 of the DSC collection of illustrative plates of the crystal form B of the compound of the Formulas I
It is shown substantially the same.
According to one embodiment of present invention, the single crystal diffraction data of the crystal form B of formula Compound I are as follows：
Preferably, the single crystal diffraction data of the crystal form B of formula Compound I with it is essentially identical shown in Fig. 5.
Another object of the present invention is to provide the methods of the crystal form A or B that prepare above-mentioned compound of formula I.
In one embodiment of the invention, the preparation method of the crystal form A of the compound of formula I includes：
1) compound of formula I of solid form is dissolved in good solvent and forms clear solution；
2) and then into the clear solution anti-solvent is added；
3) the crystal form A of compound of formula I is precipitated in stirring；
Or it stands to the crystal form A that compound of formula I is precipitated.
In the embodiment of crystal form A for preparing formula Compound I, above-mentioned steps 1) described in good solvent include but not
It is limited to organic solvent, organic solvent includes the hydro carbons with 1-10 carbon atom, alcohols, ketone, ethers, esters, nitrile, sulfone
Class, amides and nitrogen heterocycles；Or the mixed solvent formed by above-mentioned solvent；Wherein, the hydrocarbon with 1-10 carbon atom
Class includes alkyl halide hydro carbons and aromatic hydrocarbons；Ethers includes chain ethers and ring-type ethers；The chain ethers include furans；Institute
It includes tetrahydrofuran derivatives to state furans；The ring-type ethers dioxane class；Specific such as methanol, ethyl alcohol, acetone, tetrahydrochysene furan
It mutters, acetonitrile, dimethyl sulfoxide, isopropanol, methyl iso-butyl ketone (MIBK), ethyl acetate, isopropyl acetate, methyl tertiary butyl ether(MTBE), 1,4- bis-
Six ring of oxygen, methyl phenyl ethers anisole, cyclopentyl methyl ether, toluene, chloroform, or mixed by what two or more in above-mentioned solvent were formed
Bonding solvent.
In the embodiment of crystal form A for preparing formula Compound I, the anti-solvent described in step 2) includes but not limited to
Inorganic solvent and organic solvent, or the mixed solvent that is formed by above-mentioned solvent；Inorganic solvent such as water；Organic solvent is for example
Hydro carbons with 1-10 carbon atom, including alkanes, olefines, alkynes class etc..The anti-solvent of use includes n-hexane, positive heptan
Alkane, hexamethylene etc., or by two or more mixed solvents formed in above-mentioned solvent.
In the embodiment of crystal form A for preparing formula Compound I, the compound of the Formulas I and the weight of good solvent
Volume ratio (mg/mL) is (1-80):1, preferably (10-60):1.
In preparing embodiment, the volume ratio of the anti-solvent and good solvent is 1:(1-20), preferably 1:(1-10).
In the embodiment of crystal form A for preparing formula Compound I, the compound of formula I of solid form is dissolved in good
Clear solution is formed in solvent, it can optionally, such as according to actual environment temperature or condition, to compound of formula I and good solvent shape
At solution using heating by the way of promote to dissolve, obtain clear solution after can also optionally filtering solution.
Wherein, step 1) is described, and temperature when optionally being heated is 30 DEG C -80 DEG C, preferably 30 DEG C -60 DEG C, more excellent
Select 40 DEG C -50 DEG C.
Wherein, the step 3) stirring uses room temperature or cryogenic conditions；
Preferably, the step 3) cryogenic conditions are 0-20 DEG C；It is preferred that 0-10 DEG C；Further preferred 0 DEG C, 5 DEG C or 10 DEG C；
Step 3) stands to use and place at room temperature；
Step 3) stands preferred placement while slowly solvent flashing.
The present invention also provides the preparation methods of the crystal form B of the compound of formula I, including two methods：
The preparation method one of the crystal form B of compound of formula I：The compound of Formulas I is added in solvent and obtains suspension, in room temperature
It stirs, then isolated compound of formula I crystal form B.
The preparation method two of the crystal form B of compound of formula I：Compound of formula I is added into solvent, heating stirring keeps its molten
Solution, gained clear solution is placed, slow cooling, obtains compound of formula I crystal form B.
In the preparation method one and preparation method two of the crystal form B of formula Compound I, the solvent includes but unlimited
In inorganic solvent (such as water) and organic solvent；The organic solvent is alcohols, ketone, hydrocarbon with 1-10 carbon atom
Class, ethers, esters, nitrile, amides and organic acid；Preferably, the hydro carbons includes alkanes, alkyl halide hydro carbons, alkene
Class, alkynes class and aromatic hydrocarbons；Preferably, ethers includes chain ethers and ring-type ethers, and the chain ethers include furans；Institute
It includes tetrahydrofuran derivatives to state furans；The ring-type ethers dioxane class.
Preferably, the preferred methyl tertiary butyl ether(MTBE) of the solvent, isopropanol, ethyl alcohol, isobutyl ester acetic acid, n-hexane, methanol, third
Ketone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, 2- methyltetrahydrofurans, dichloromethane, ethyl acetate, toluene, or selected from above-mentioned
The mixed solvent of two or more in solvent.
In the preparation method one and preparation method two of the crystal form B of formula Compound I, the mixed solvent is esters
The mixed solvent of solvent, hydrocarbon solvent, esters solvent：Hydrocarbon solvent volume ratio is 1-10:1.
In the preparation method one and preparation method two of formula Compound I crystal form B, the compound of formula I and solvent
W/v be calculated as (1-200) by mg/mL:1, preferably (50-150):1.
It is described in the preparation method two of the crystal form B of compound of formula I prepares the embodiment of crystal form using slow cooling method
The cooling rate of slow cooling is 0.1-0.5 DEG C/min, preferably 0.1-0.3 DEG C/min, more preferable 0.1 DEG C/min.
In the embodiment of the preparation method two of the crystal form B of compound of formula I, the heating temperature is 30-80 DEG C, preferably
40-70 DEG C, such as 45 DEG C, 50 DEG C, 55 DEG C, 60 DEG C.
In the embodiment of the preparation method two of the crystal form B of compound of formula I, the temperature at the end of the cooling is room temperature
Or 0-10 DEG C, such as 3 DEG C, 5 DEG C, 7 DEG C.
In the embodiment of the preparation method two of the crystal form B of compound of formula I, the compound of the Formulas I and the weight of solvent
It is (1-500) to measure volume ratio (mg/mL):1, preferably (100-400):1.
It is a further object of the present invention to provide a kind of new pharmaceutical compositions, and it includes the crystal form A of compound of formula I, Formulas I
It closes the crystal form B of object or it is arbitrarily combined and one or more pharmaceutically acceptable carriers.
It is a further object of the present invention to provide the crystal form B of the crystal form A of compound of formula I and compound of formula I or it is arbitrary
Combine the purposes in the drug for preparing treatment Hepatitis C Virus (HCV) NS5B polymerase inhibitors.
It is yet another object of the invention to provide the crystal form B of the crystal form A of compound of formula I and compound of formula I or it is arbitrary
Combine the purposes in the drug for preparing treatment hepatitis C disease.
In above-mentioned pharmaceutical applications, the crystal form A of compound of formula I, the crystal form B of compound of formula I or its arbitrary combination use
Effective quantity is administered.
As used herein, the term " pharmaceutically acceptable carrier " refer to the diluent being administered together with therapeutic agent,
Adjuvant, excipient or medium, and it is adapted for contact with the mankind and/or other animals in the range of rational medical judgment
Tissue without excessive toxicity, stimulation, allergic reaction or with rational benefit/risk compared with corresponding other problems or concurrently
Disease.
Workable pharmaceutically acceptable carrier includes but not limited to sterile liquid in the pharmaceutical composition of the present invention,
Such as water and oil, including those oil, animal, plant or synthesis source oil, such as soybean oil, peanut oil, mineral oil etc..When
When described pharmaceutical composition is administered intravenously (IV, water is exemplary carrier.Physiological saline and glucose and sweet can also be used
Oil solution is especially used for injection as liquid-carrier.Suitable drug excipient includes glucose, starch, lactose, bright
Glue, maltose, sucrose, chalk, silica gel, glycerin monostearate, odium stearate, talcum, sodium chloride, glycerine, propylene glycol, water,
Ethyl alcohol etc..The composition can also include optionally a small amount of wetting agent, emulsifier or pH buffer.Oral preparation can wrap
Containing standard vector, such as the mannitol of pharmaceutical grade, lactose, starch, magnesium stearate, cellulose, saccharin sodium, magnesium carbonate.Suitable
The example of pharmaceutically acceptable carrier is as described in Remington ' s Pharmaceutical Sciences (1990).
The pharmaceutical composition of the present invention can be acted on systematically and/or locally be acted on.For this purpose, they can be suitble to
Approach administration, such as by injection, intra-arterial, subcutaneous, intravenous, peritonaeum, intramuscular or percutaneous dosing；Or by taking orally,
Intranasal, it is buccal, transmucosal, local, in the form of eye-drops preparations or pass through inhalation.
For these administration routes, the adoptable dosage form of pharmaceutical composition of the present invention include but not limited to tablet, capsule,
Pastille, hard candy agent, powder, spray, cream, ointment, suppository, gelling agent, aqueous suspension, injection, elixir, syrup
Agent.
Pharmaceutical composition of the present invention can be prepared by any method well known in the art, such as by mixed
Conjunction, granulation, the processing such as sweet tablet, mills, emulsifies, being lyophilized to prepare at dissolving." treatment is effective as used herein, the term
Amount " refers to the amount of the compound for one or more symptoms that can alleviate treated illness after being administered to a certain extent.
Adjustable dosage regimen is to provide optimal required response.For example, single bolus can be administered, can be administered at any time several
Divided dose, or can be proportionally reduced as indicated in the urgent need for the treatment of or incremental dose.It should be noted that dose value can be with will subtract
The type and seriousness of the light patient's condition and change, and may include single or multiple dosage.It further understands, for any specific
Individual, specific dosage regimen should be sentenced according to the profession of individual need and administration composition or the personnel for the administration for supervising composition
Break to adjust at any time.
The amount of the compound of the present invention being administered can depend on individual treated, the seriousness of illness or the patient's condition, to
The disposition of the rate, compound of medicine and the judgement of prescriber.In general, effective dose is in per kg body weight per day about 0.0001
To about 100mg, for example, about 0.01 to about 10mg/kg/ days (single or divided doses).For the people of 70kg, add up to about
0.007mg/ to about 7000mg/, for example, about 0.7mg/ to about 700mg/.In some cases, it is not higher than aforementioned model
The dosage level of the lower limit enclosed can be enough, and in other cases, it still can be in the feelings for not causing any harmful side effect
Larger dose is used under condition, condition is that the larger dose is divided into several smaller doses to be administered throughout the day first.
Content or dosage of the compound of the present invention in pharmaceutical composition can be about 0.01mg to about 1000mg, be suitble to
Ground is 0.1-500mg, preferably 0.5-300mg, more preferable 1-150mg, particularly preferred 1-50mg, for example, 1.5mg, 2mg, 4mg,
10mg and 25mg etc..
Unless otherwise stated, otherwise as used herein, term " treatment (treating) " means to reverse, mitigate, suppression
The progress for the illness or the patient's condition or one or more symptoms of such illness or the patient's condition that the such term of system is applied, or prevent
One or more symptoms of such illness or the patient's condition or such illness or the patient's condition.
" individual " includes people or non-human animal as used herein.Exemplary individual human include with disease (such as this
Disease described in text) individual human (be known as patient) or normal individual." non-human animal " includes all vertebrates in the present invention,
Such as nonmammalian (such as amphibian, reptile, birds) and mammal, such as non-human primates, domestic animal and/or
Domestication animal (such as dog, cat, sheep, milk cow, pig etc.).
Description of the drawings
The powder diffraction spectrum of the crystal form A of Fig. 1 nucleoside phosphoramidite class compounds.
The DSC collection of illustrative plates of the crystal form A of Fig. 2 nucleoside phosphoramidite class compounds.
The powder diffraction spectrum of the crystal form B of Fig. 3 nucleoside phosphoramidite class compounds.
The DSC collection of illustrative plates of the crystal form B of Fig. 4 nucleoside phosphoramidite class compounds.
The single crystal diffraction figure of the crystal form B of Fig. 5 nucleoside phosphoramidite class compounds.
Specific implementation mode
Definition
Unless hereinafter defined otherwise, the meaning of all technical terms and scientific terms used herein is intended to and this
Field technology personnel are generally understood identical.It refers to that technology used herein is intended to refer to be generally understood in the art
Technology, including the variation of those technologies that will be apparent to those skilled in the art or the replacement of equivalence techniques.While it is believed that with
Lower term is for those skilled in the art it is well understood that but still illustrating defined below preferably to explain the present invention.
"include", "comprise", " having ", " containing " or " being related to " and its herein as used herein, the term
Other variant forms are the (inclusive) or open of inclusive, and are not excluded for other unrequited elements or method step
Suddenly.
Word as used herein refers to " about " that those skilled in the art think in the acceptable of described value
Standard error in, such as ± 0.05, ± 0.1, ± 0.2, ± 0.3, ± 1, ± 2, ± 3 or ± 4 etc..
" crystal form " or " crystal " refers to the arbitrary solid matter that three-dimensional sequence is presented as used herein, the term, with nothing
White amorphous solid substance is on the contrary, it generates the characteristic XRPD collection of illustrative plates at the peak with clear border.
" X-ray powder diffraction pattern (XRPD collection of illustrative plates) " refers to the diffraction pattern of Germicidal efficacy as used herein, the term
Or the parameter derived from it.XRPD collection of illustrative plates is usually characterized by peak position (abscissa) and/or peak intensity (ordinate).
" 2 θ " refers to being indicated with the number of degrees for the experimental setup based on x-ray diffraction experiment as used herein, the term
Peak position, and be typically the abscissa unit in diffracting spectrum.If reflecting quilt when incident beam and certain lattice plane shape are into θ angle
Diffraction, then experimental setup needs are with 2 angles θ record reflecting bundle.It should be appreciated that the particular crystalline mentioned herein is specific
2 θ values are intended to indicate using 2 θ values (being indicated with the number of degrees) measured by x-ray diffraction experiment condition as described herein.For example, such as this
Described in text, using Cu-K α (1.540598 and1.544426) it is used as radiation source.
" differential scanning calorimetry (DSC) collection of illustrative plates " refers to being recorded by differential scanning calorimeter as used herein, the term
Curve.
As used herein, the term " substantially the same " of X-ray diffraction peak position is meant representative peak position
It is taken into account with Strength Changes.For example, it will be understood by those skilled in the art that peak position (2 θ) can show some variations, usually up to
0.1-0.2 degree, and the instrument for measuring diffraction can also show some variations.In addition, it will be understood by those skilled in the art that phase
Between peak intensity can be display instrument variation and due to crystallinity degree, preferred orientation, the sample surfaces of preparation and ability
The variation of other factors known to field technique personnel, and should be regarded as only observational measurement.Similarly, as made herein
With being also intended to cover for " substantially the same " of DSC collection of illustrative plates well known by persons skilled in the art related with these analytical technologies
Variation.For example, for the peak of clear border, there would generally be up to ± 0.2 DEG C of variation in Differential Scanning Calorimetry, it is right
In broad peak even bigger (such as up to ± 1 DEG C).
" good solvent " means the compound of formula I for dissolving the present invention or Formulas I chemical combination as used herein, the term
The solvent of the salt of object.
" anti-solvent " means deliquescent in good solvent for reducing object to be crystallized as used herein, the term
Solvent.
" hydro carbons " preferably means the hydrocarbon with 1-10 carbon atom as used herein, the term comprising alkanes,
Alkyl halide hydro carbons, olefines, alkynes class and aromatic hydrocarbons, including but not limited to dichloromethane, chloroform (chloroform), n-hexane,
Normal heptane and toluene.
" alcohols " preferably means the alcohol with 1-10 carbon atom as used herein, the term comprising but be not limited to
Methanol, ethyl alcohol, 1- propyl alcohol (normal propyl alcohol), 2- propyl alcohol (isopropanol), n-butyl alcohol, 2- butanol and the tert-butyl alcohol.
" ethers " preferably means the ether with 2-6 carbon atom as used herein, the term comprising chain ethers
With ring-type ethers (such as furans (including tetrahydrofuran derivatives) and dioxane class), it is specifically including but not limited to ether, two different
Propyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, 2- methyltetrahydrofurans, dioxane, cyclopentyl methyl ether, methyl phenyl ethers anisole and diformazan
Oxygroup ethane.
" nitrile " preferably means the nitrile with 2-6 carbon atom as used herein, the term comprising but be not limited to
Acetonitrile and propionitrile.
" ketone " preferably means the ketone with 2-6 carbon atom as used herein, the term comprising but be not limited to
Acetone, butanone, methyl ethyl ketone, methyl iso-butyl ketone (MIBK) and metacetone.
" esters " preferably mean the ester with 3-10 carbon atom as used herein, the term comprising but be not limited to
Ethyl acetate, propyl acetate, isopropyl acetate, isopropyl acetoacetic ester, dimethyl carbonate and butyl acetate.
" organic acid " preferably means the organic acid with 1-10 carbon atom as used herein, the term comprising
But it is not limited to formic acid and acetic acid.
" sulfone class " preferably means the sulfone or sulfoxide with 2-10 carbon atom as used herein, the term comprising but
It is not limited to dimethyl sulfoxide (DMSO).
" amides " preferably mean the amide with 1-10 carbon atom as used herein, the term comprising but not
It is limited to dimethylformamide or dimethylacetylamide.
" nitrogen heterocycles " preferably mean former with 3-10 carbon atom and at least one nitrogen as used herein, the term
The nitrogen heterocyclic ring of son comprising but it is not limited to N-Methyl pyrrolidone.
Numberical range (such as " 1-10 ") as used herein and its subrange are (such as " 2-10 ", " 2-6 ", " 3-
10 ") etc. cover in the numberical range it is arbitrary (such as 1,2,3,4,5,6,7,8,9 or
10).
Can by the crystal form of the compound of formula I of preparation, compound of formula I crystal form by include decantation, centrifugation, steam
Hair, gravity filtration, suction filtration or under elevated pressure or under reduced pressure it is any other for solid recycling technology including method
It is recycled.The solid of recycling can be optionally dried." drying " in the present invention be under decompression (preferably vacuum) into
Row is reduced to International Conference on Harmonisation of until the content of residual solvent
Technical Requirements for Registration of Pharmaceuticals for Human Use
In the range of limit given by (" ICH ") guide.Residual solvent levels depend on the type of solvent, but no more than about
5000ppm or preferably from about 4000ppm or more preferably from about 3000ppm.The drying can pan dryer, vacuum drying oven,
Air -oven, conical vacuum drier (cone vacuum dryer), rotary vacuum dryer, fluidized bed dryer, rotation
It is carried out in flash distillation dryer, flash dryer etc..The drying can below about 100 DEG C, below about 80 DEG C, be below about 60
DEG C, below about at 50 DEG C, the temperature below about 30 DEG C or any other suitable temperature, in atmospheric pressure or decompression (preferably vacuum)
Under within any desired time that can realize desired result (such as from about 1,2,3,5,10,15,20,24 hour or overnight)
It carries out, as long as the quality of product does not deteriorate.The drying can carry out any desired number, until realizing required product product
Matter.Dry product can be optionally subjected to crushing operation, to generate desired granularity.It before the drying of product or can dry
It is ground or is micronized after.The technology that can be used for reducing granularity includes but not limited to ball milling, roller mill and sledge mill, and injection
Grinding.
The present invention is explained in greater detail below with reference to embodiment, the embodiment of the present invention is merely to illustrate the skill of the present invention
Art scheme, is not intended to limit the scope of the present invention, and those skilled in the art can carry out some nonessential modifications and adaptations, still
It belongs to the scope of protection of the present invention.
Experiment test equipment information and method used
Method 1, XRPD
XRPD collection of illustrative plates acquires on PANalyticalEmpyrean X-ray powder diffraction analyzers, and the X of XRPD tests is penetrated
Line be Cu-k α (1.540598；1.544426；1 intensities of K α 2/K α：0.50).
Method 2, dsc analysis
DSC data is acquired on TAQ200/2000 differential scanning calorimeters.
Method 3, ion chromatography (IC)
Using ion chromatography (IC) to measure gegenion content, and itself and HPLC are combined to determine the salt Chinese style of gained
The molar ratio of Compound I and salt-forming ion.
Preparation example：
The preparation of compound of formula I
(1) phosphorus oxychloride (10mmol) is dissolved in dichloromethane (10mL), is cooled to -60 DEG C, 4- hydroxyls -7- is slowly added dropwise
The dichloromethane solution (10mL) of Fluorobenzofur (10mmol) and triethylamine (10mmol).It is added dropwise, removes cryostat, rise to
25 DEG C are stirred 2 hours.Reaction system is further cooled to -60 DEG C, l-Alanine isopropyl ester hydrochloride (9mmol) is added, so
The dichloromethane solution (5mL) of triethylamine (25mmol) is added dropwise afterwards.It is added dropwise, removes cryostat, rise to 25 DEG C and stir 2 hours.
Reaction system is further cooled to -60 DEG C, the dichloromethane solution of Pentafluorophenol (9mmol) and triethylamine (15mmol) is added dropwise
(10mL).It is added dropwise, removes cryostat, rise to 25 DEG C and stir 2 hours.The reaction was complete, and reaction system is poured into ice water, with two
Chloromethanes extracts.It collects merging organic phase to be washed with saturated common salt aqueous solution, dry, filtering and concentrating obtains intermediate d.
(2) by 1- (the fluoro- 4- hydroxyls -5- methylols -3- methyltetrahydrofurans -2- bases of (2R, 3R, 4R, 5R) -3-) pyrimidine -
2,4- (1H, 3H)-diketone (1mmol) are dissolved in anhydrous tetrahydro furan (20mL), and argon gas is replaced three times.Tertiary butyl is added dropwise in 0 DEG C
Magnesium chloride (1.0mol/L, 2.5mL, 2.5mmol) rises to 25 DEG C and reacts 1 hour.It is cooled to 0 DEG C, above-mentioned intermediate compound is added dropwise
Object (S)-isopropyl -2- (((phenyl-pentafluoride oxygroup) (2,3- Dihydrobenzofuranes -6- oxygroups) phosphoryl) amino) propionic ester
Anhydrous tetrahydro furan (10mL) solution of (1mmol).It is added dropwise, is warmed to room temperature reaction 15 hours.Be added dropwise few drops of 2M hydrochloric acid to
Reaction system becomes clarification.Water 30mL is added to dilute, 2M hydrochloric acid is adjusted to neutrality.Reaction system is extracted with ethyl acetate, and collection is associated with
Machine mutually uses saturated sodium bicarbonate aqueous solution respectively, and saturated common salt water washing is dry, and filtering and concentrating, residue is purified through column chromatography, obtained
To intermediate e (yield 55%).Intermediate e is obtained into compound of formula I through preparing chromatographic isolation.
Its structural characterization is as follows：
ESI-MS:m/z 588.2(M++H)
1H NMR(400MHz,CDCl3)：δ 9.13 (s, 1H), 7.66-7.65 (d, J=4.0Hz, 1H), 7.47-7.45 (d,
J=8.0Hz, 1H), 7.09-7.08 (m, 1H), 7.00-6.95 (m, 2H), 6.17-6.13 (d, J=16.0Hz, 1H), 5.74-
5.72 (d, J=8.0Hz, 1H), 5.72-4.95 (m, 1H), 4.53-4.45 (m, 2H), 4.19-4.11 (m, 2H), 3.99-3.92
(m,2H),2.36(s,1H),1.43–1.33(m,6H),1.24–1.17(m,6H).
31P-NMR(CD3OD,162MHz):δ3.95。
1 preparation of compounds of formula I crystal form A of embodiment
The ethyl acetate of 10ml is added in 5g compound of formula I, then heating stirring is dripped to 45 DEG C~50 DEG C dissolving clarifications
Add the n-hexane of 5ml, for slow cooling to 0 DEG C~5 DEG C crystallizations, filtration drying obtains compound of formula I crystal form A3.4g, yield about 68%.
Analysis is detected to gained compound of formula I crystal form A, gained XRPD collection of illustrative plates is as shown in Figure 1, gained DSC collection of illustrative plates is as shown in Figure 2.
2 preparation of compounds of formula I crystal form B of embodiment
The mixed solvent of 60mL ethyl acetate and 30mL n-hexanes is added in modus ponens Compound I crystal form A, 10g thereto, obtains
Suspension in 20 DEG C~25 DEG C stirring and crystallizings, filtering, lower 45 DEG C~50 DEG C of vacuum drying 4 hours obtains type I compound crystal form
B7.6g, yield about 76%.
Analysis is detected to gained type I compound crystal form B, gained XRPD collection of illustrative plates as shown in figure 3, gained DSC collection of illustrative plates such as
Shown in Fig. 4.
3 preparation of compounds of formula I crystal form B of embodiment
Add 25mL isopropanols to be heated to 55 DEG C~60 DEG C type I compound 5g, stirs dissolved clarification, slow cooling is to 0 DEG C~5 DEG C
Crystallization, filtering, the drying 4 hours of lower 45 DEG C~50 DEG C of vacuum obtain type I compound crystal form B3.6g, yield 72%.
The XRPD collection of illustrative plates and DSC collection of illustrative plates of gained type I compound crystal form B and the XRPD collection of illustrative plates and DSC collection of illustrative plates bases in embodiment 2
It is identical in sheet, show to have obtained type I compound crystal form B.
4 preparation of compounds of formula I crystal form B of embodiment
Add 15mL ethyl alcohol to be heated to 55 DEG C~60 DEG C type I compound 5g, stirs dissolved clarification, slow cooling to 0 DEG C~5 DEG C analysis
Crystalline substance, filtering, the dry 4h of lower 45 DEG C~50 DEG C of vacuum obtain type I compound crystal form B3.4g, yield about 68%.
The XRPD collection of illustrative plates and DSC collection of illustrative plates of gained type I compound crystal form B and the XRPD collection of illustrative plates and DSC collection of illustrative plates bases in embodiment 2
It is identical in sheet, show to have obtained type I compound crystal form B.
5 preparation of compounds of formula I crystal form B of embodiment
Add 15mL acetonitriles to be heated to 55 DEG C~60 DEG C type I compound 5g, stirs dissolved clarification, slow cooling to 0 DEG C~5 DEG C analysis
Crystalline substance, filtering, the dry 4h of lower 45 DEG C~50 DEG C of vacuum obtain type I compound crystal form B 3.5g, yield about 70%.
The XRPD collection of illustrative plates and DSC collection of illustrative plates of gained type I compound crystal form B and the XRPD collection of illustrative plates and DSC collection of illustrative plates implemented in 2 are basic
It is upper identical, show to have obtained type I compound crystal form B.
Following experimental example is illustrating the advantageous effect of formula I compound crystal form A and type I compound crystal form B.
Experimental example 1
1.) hERG is detected
Method：Using fluorescence polarization method, assesses crystal form A and B of the present invention and potentially cause QT (QRS complex starting points to T wave ends
The time of point) interval prolongation effect.Crystal form A and crystal form B/ positive reference substances/the moon of the present invention is sequentially added in porous plate
Property reference substance, the membrane-bound fragment containing the channels hERG, the tracer with the channels hERG with high affinity, 25 DEG C, 250rpm is (every
Revolutions per minute) it is incubated 4 hours.The fluorescence polarization value in each hole is measured with multi-function microplate reader, and it is logical to hERG to calculate crystal form of the present invention
The relative inhibition in road and 50% inhibition concentration (IC50).Experimental result is shown in Table 1.
1 external hERG histamine results of table
As a result it shows：Crystal form A shown in the present invention and crystal form B are respectively less than 50% under 30 μM of concentration to hERG inhibiting rates,
And the IC of crystal form of the present invention5030 μM are all higher than, shows do not have hERG toxicity.
2.) mitochondrial toxicity
Method：Using chemiluminescence method, influence of the crystal form of the present invention to mitochondrial toxicity is assessed.It is thin to collect cell adjustment
A concentration of 2*10 of born of the same parents' bed board5A/mL is separately added into crystal form of the present invention and control drug stimulation cell, in 37 DEG C, 5%CO2
Incubator in be incubated 2h.It is incubated and completes, be placed at room temperature for 5min, 100ul ATP detection reagents are added per hole, 500-on shaking table
700rpm mixings 5min.In detecting chemiluminescence signal on BMG PHARStar.It the results are shown in Table 2.
Table 2
Experimental result according to the present invention is shown：Crystal form A of the present invention is compared with control drug Suo Feibuwei in cytotoxicity
With lower on mitochondrial toxicity, and crystal form A of the present invention equal no cytotoxicity and mitochondrial toxicity under no more than 10 μM concentration.
3.) cytotoxicity
Method：Collect a concentration of 2*10 of cell adjustment plating cells^4A/hole, in 37 DEG C, 5%CO2Incubator in be incubated
4h.Compound shown in following table is added to orifice plate moderate stimulation cell, continues to be incubated 40h, discards Incubating Solution later, respectively wait for that gaging hole adds
Complete 100 holes μ l/ of culture medium, are incubated in incubator and stablize 0.5-1h, 10 holes μ l/ MTS solution are added later, continue to incubate in incubator
Educate 4h.Absorbance is measured in 450nm wavelength.It the results are shown in Table 3.
Table 3
| IC50(μM) | HEK293 | Jurkat | HK-2 | N2a |
| Tamoxifen | 48.95uM | 6.62uM | 28.78uM | 23.36uM |
| Crystal form A | ＞ 50uM | ＞ 50uM | ＞ 50uM | ＞ 50uM |
| Crystal form B | ＞ 50uM | ＞ 50uM | ＞ 50uM | ＞ 50uM |
Remarks：HEK293 indicates human embryonic kidney cells in table 3；Jurkat indicates human peripheral leukemia T cell；HK-2 is indicated
People's proximal tubular cell；N2a indicates neuroma mother cell.
As a result it shows：Crystal form A and B of the present invention is smaller in the different cytotoxics of human body, when using tamoxifen as
When positive control, the toxicity smaller of product of the present invention, with very excellent safety when patient uses.
The horizontal medicine efficacy screening method of experimental example 2HCV replicon model cells and data
Two steady cell lines that turn containing HCV replicons can be used for detecting the anti-hepatitis C virus work of crystal form A and crystal form B of the present invention
Property.Liver cancer cell lines Huh7-Con1b includes the duplication of HCV genotype (GT) 1b Con1b firefly luciferase reporter genes
Son；Cell line Huh7-H77 includes the replicon of GT1a H77Renilla luciferase reporter genes.Thus, crystal form A of the present invention
It can be verified by marker examining report gene activity with the crystal form B effects for inhibiting HCV to replicate.Drug activity testing number
According to being shown in Table 4.
Table 4
Upper table data show that crystal form of the invention has the therapeutic activity of outstanding hepatitis C virus, and also has in contrast
There is very small cytotoxicity.
Experimental example 3, pharmacokinetics in rats research
Male SD rat Suo Feibuwei and crystal form A and B of the present invention are given by single oral gavage respectively, investigates three in liver
The metabolic rule of phosphate metabolism product.Dosage is 50mg/kg, and vehicle system is 10%DMSO:10%solutol:
80% water.After P of Rats O administration respectively at 2,4,8, put to death for 24 hours, collect blood and hepatic tissue.Immediately with 5 times after hepatic tissue taking-up
The homogenate of the precooling of volume is homogenized, and homogenate is methanol：20mM EDTA aqueous solutions (7:3, V/V).The rat of above compound
PK results of study are shown in table 5.
Table 5：The concentration mensuration result of rat liver triphosphoric acid metabolin
As shown in Table 5, crystal form of the invention can be smoothly metabolized in rat body, and generate active triphosphoric acid
Nucleoside metabolism substance is efficiently used by body and generates corresponding active function.
Claims (10)
1. the crystal form A of nucleoside phosphoramidite class compound, it is characterised in that：2 angles θ of feature of its powder diffraction are included in 3.10 ±
0.2°、6.78±0.2°、10.43±0.2°、11.32±0.2°、12.58±0.2°、13.72±0.2°、17.27±0.2°、
Characteristic peak at 18.28 ± 0.2 ° of the angle of diffraction (2 θ)；
Preferably, 2 angles θ of feature of powder diffraction be included in 3.10 ± 0.2 °, 6.78 ± 0.2 °, 10.43 ± 0.2 °, 11.32
±0.2°、11.79±0.2°、12.58±0.2°、13.72±0.2°、15.50±0.2°、17.27±0.2°、17.67±
0.2 °, 18.28 ± 0.2 °, 23.07 ± 0.2 °, the characteristic peak at 23.51 ± 0.2 ° of the angle of diffraction (2 θ)；
It is furthermore preferred that 2 angles θ of feature of its powder diffraction be included in 3.10 ± 0.2 °, 6.78 ± 0.2 °, 10.43 ± 0.2 °,
11.32±0.2°、11.79±0.2°、12.58±0.2°、13.72±0.2°、14.68±0.2°、15.50±0.2°、17.27
±0.2°、17.67±0.2°、18.28±0.2°、19.44±0.2°、20.94±0.2°、23.07±0.2°、23.51±
0.2 °, 25.13 ± 0.2 °, 25.90 ± 0.2 °, 26.64 ± 0.2 °, 26.87 ± 0.2 ° and 28.38 ± 0.2 ° of the angle of diffraction (2 θ)
The characteristic peak at place；
Preferably, the XRPD peak positions of crystal form A are substantially the same with shown in Fig. 1.
2. the crystal form A of nucleoside phosphoramidite class compound according to claim 1, it is characterised in that：DSC collection of illustrative plates is included in about
126.93 the characteristic peak at DEG C.
3. the preparation method of the crystal form A of nucleoside phosphoramidite class compound as claimed in claim 1 or 2, it is characterised in that：Nucleosides phosphorus
Amides compound is compound of formula I, and structural formula is as follows：
Include the following steps：
1) compound of formula I of solid form is dissolved in good solvent and forms clear solution；
2) and then into the clear solution anti-solvent is added；
3) the crystal form A of compound of formula I is precipitated in stirring；
Or it stands to the crystal form A that compound of formula I is precipitated.
4. the preparation method of the crystal form A of nucleoside phosphoramidite class compound according to claim 3, it is characterised in that：At least
Meet following any one：
Step 3) the stirring uses room temperature or cryogenic conditions；
Preferably, the step 3) cryogenic conditions are 0-20 DEG C；It is preferred that 0-10 DEG C；Further preferred 0 DEG C, 5 DEG C or 10 DEG C；
Step 3) stands to use and place at room temperature；
Step 3) stands preferred placement while slowly solvent flashing；
Good solvent described in step 1) includes but not limited to organic solvent；
Step 1) the organic solvent includes the hydro carbons with 1-10 carbon atom, alcohols, ketone, ethers, esters, nitrile, sulfone
Class, amides and nitrogen heterocycles；Or the mixed solvent formed by above-mentioned solvent；
Preferably, the step 1) hydro carbons with 1-10 carbon atom includes alkyl halide hydro carbons and aromatic hydrocarbons；
Preferably, the step 1) ethers includes chain ethers and ring-type ethers；Further, the chain ethers include furans
Class；Further, the furans include tetrahydrofuran derivatives；Further, the ring-type ethers dioxane class；
Preferably, the step 1) organic solvent includes methanol, ethyl alcohol, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, isopropyl
Alcohol, methyl iso-butyl ketone (MIBK), ethyl acetate, isopropyl acetate, methyl tertiary butyl ether(MTBE), 1,4- dioxane, methyl phenyl ethers anisole, cyclopenta first
Ether, toluene, chloroform, or by two or more mixed solvents formed in above-mentioned solvent；
Anti-solvent described in step 2) includes but not limited to inorganic solvent, organic solvent；Or the mixing formed by above-mentioned solvent
Solvent；
Anti-solvent inorganic solvent described in step 2) is water；
Anti-solvent organic solvent described in step 2) includes the hydro carbons for having 1-10 carbon atom；
It includes alkanes, olefines, alkynes class that anti-solvent described in step 2), which has the hydro carbons of 1-10 carbon atom,；
Anti-solvent described in step 2) is n-hexane, normal heptane, hexamethylene or by two or more shapes in above-mentioned solvent
At mixed solvent；
The w/v of the compound of formula I and good solvent is calculated by mg/mL, is 1-80:1；It is preferred that 10-60:1；
The anti-solvent and the volume ratio of good solvent are 1:1-20, preferably 1:1-10；
Step 1) prepares clear solution by the way of the solution that heating compound of formula I and good solvent are formed；
Further, heating temperature is 30 DEG C -80 DEG C, preferably 30 DEG C -60 DEG C, more preferable 40 DEG C -50 DEG C；
Step 1) prepares after clear solution filters solution and obtains clear solution.
5. the crystal form B of nucleoside phosphoramidite class compound, it is characterised in that：2 angles θ of feature of its powder diffraction are included in 3.10 ±
0.2°、6.75±0.2°、9.01±0.2°、10.10±0.2°、11.06±0.2°、11.81±0.2°、14.17±0.2°、
15.05 ± 0.2 °, 15.84 ± 0.2 °, 16.93 ± 0.2 °, 18.14 ± 0.2 °, 18.78 ± 0.2 °, 20.30 ± 0.2 ° and
Characteristic peak at 20.80 ± 0.2 ° of the angle of diffraction (2 θ)；
Preferably, 2 angles θ of feature of powder diffraction be included in 3.10 ± 0.2 °, 6.75 ± 0.2 °, 9.01 ± 0.2 °, 10.10 ±
0.2°、11.06±0.2°、11.81±0.2°、12.03±0.2°、12.84±0.2°、14.17±0.2°、15.05±0.2°、
15.57±0.2°、15.84±0.2°、16.93±0.2°、17.44±0.2°、18.14±0.2°、18.78±0.2°、20.30
Feature at ± 0.2 °, 20.80 ± 0.2 °, 21.78 ± 0.2 °, 22.44 ± 0.2 ° and 23.11 ± 0.2 ° of the angle of diffraction (2 θ)
Peak；
It is furthermore preferred that 2 angles θ of feature of its powder diffraction be included in 3.10 ± 0.2 °, 6.75 ± 0.2 °, 9.01 ± 0.2 °, 10.10
±0.2°、11.06±0.2°、11.81±0.2°、12.03±0.2°、12.84±0.2°、14.17±0.2°、15.05±
0.2°、15.57±0.2°、15.84±0.2°、16.93±0.2°、17.44±0.2°、18.14±0.2°、18.78±0.2°、
19.28±0.2°、20.30±0.2°、20.80±0.2°、21.78±0.2°、22.26±0.2°、22.44±0.2°、23.11
±0.2°、23.55±0.2°、24.86±0.2°、26.17±0.2°、27.27±0.2°、27.78±0.2°、30.62±
Characteristic peak at 0.2 °, 31.02 ± 0.2 °, 31.40 ± 0.2 ° and 34.34 ± 0.2 ° of the angle of diffraction (2 θ)；
Preferably, the XRPD peak positions of crystal form B are substantially the same as shown in figure 3.
6. the crystal form B of nucleoside phosphoramidite class compound according to claim 5, it is characterised in that：At least meet following appoint
Meaning one：
DSC collection of illustrative plates is included in the characteristic peak at about 141.3 DEG C；
The single crystal diffraction data of the crystal form B of the nucleoside phosphoramidite class compound are：
7. the preparation method of the crystal form B of nucleoside phosphoramidite class compound described in claim 5 or 6, it is characterised in that：
Nucleoside phosphoramidite class compound is compound of formula I, and structural formula is as follows：
Including two kinds of preparation methods：
Preparation method one：Compound of formula I is added in solvent and obtains suspension, is stirred at room temperature, then isolated Formulas I chemical combination
The crystal form B of object；
Preparation method two：Compound of formula I is added into solvent, heating stirring makes it dissolve, and gained clear solution is placed, and delays
Slow cooling, obtains the crystal form B of compound of formula I.
8. the preparation method of the crystal form B of nucleoside phosphoramidite class compound according to claim 7, it is characterised in that：At least
Meet following any one：
In preparation method one and preparation method two, the solvent includes but not limited to inorganic solvent and organic solvent；It is inorganic molten
Agent, organic solvent；Or the mixed solvent formed by above-mentioned solvent；
Preferably, in preparation method one and preparation method two, the organic solvent is alcohols, ketone with 1-10 carbon atom
Class, hydro carbons, ethers, esters, nitrile, amides and organic acid；
It is further preferred that in preparation method one and preparation method two, the hydro carbons includes alkanes, alkyl halide hydro carbons, alkene
Class, alkynes class and aromatic hydrocarbons；
It is further preferred that in preparation method one and preparation method two, ethers includes chain ethers and ring-type ethers；The chain
Ethers includes furans；The furans include tetrahydrofuran derivatives；The ring-type ethers dioxane class；
It is the preferred methyl tertiary butyl ether(MTBE) of the solvent, isopropanol, ethyl alcohol, different it is furthermore preferred that in preparation method one and preparation method two
Butyl ester acetic acid, n-hexane, methanol, acetone, tetrahydrofuran, acetonitrile, dimethyl sulfoxide, 2- methyltetrahydrofurans, dichloromethane, acetic acid
Ethyl ester, toluene, or the mixed solvent of two or more in above-mentioned solvent；
It is further preferred that in preparation method one and preparation method two, the mixed solvent be esters solvent, hydrocarbon solvent it is mixed
Bonding solvent, esters solvent：The volume ratio of hydrocarbon solvent is 1-10:1；
In preparation method one and preparation method two, the w/v of the compound of formula I and solvent is calculated as 1-200 by mg/mL:
1, preferably 50-150:1；
The cooling rate of slow cooling described in preparation method two is 0.1-0.5 DEG C/min, preferably 0.1-0.3 DEG C/min, more excellent
Select 0.1 DEG C/min；
Heating temperature described in preparation method two is 30-80 DEG C, preferably 40-70 DEG C, more preferable 45 DEG C, 50 DEG C, 55 DEG C, 60 DEG C；
Described in preparation method two cool down at the end of temperature be room temperature or 0-10 DEG C, preferably 3 DEG C, 5 DEG C, 7 DEG C；
The w/v of compound of formula I and solvent described in preparation method two is calculated as 1-500 by mg/mL:1, preferably 100-400:
1。
9. pharmaceutical composition, it is characterised in that：Including the crystal form B of the crystal form A of compound of formula I, compound of formula I or its arbitrary group
Conjunction and one or more pharmaceutically acceptable carriers.
10. the crystal form B of the crystal form A of compound of formula I, compound of formula I or its arbitrary combination are preparing treatment Hepatitis C Virus
(HCV) purposes in the drug of NS5B polymerase inhibitors；
Further preferably, the crystal form A of the compound of formula I and crystal form B of compound of formula I or its arbitrary combination are preparing treatment third
Purposes in the drug of type hepatitis disease；
It is preferred that in above-mentioned pharmaceutical applications, the crystal form A of compound of formula I, the crystal form B of compound of formula I or its arbitrary combination use
Effective quantity is administered.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113058076A (en) * | 2021-03-29 | 2021-07-02 | 四川大学 | Supermolecule nucleoside hydrogel and preparation method and application thereof |
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| CN104130302A (en) * | 2014-08-08 | 2014-11-05 | 广东东阳光药业有限公司 | Crystal form of nucleotide medicines and preparation method of crystal form |
| CN104231023A (en) * | 2013-06-06 | 2014-12-24 | 南京圣和药业有限公司 | Tricyclic fused-heterocyclic nucleoside phosphoramidate compound and preparation method and applications of tricyclic fused-heterocyclic nucleoside phosphoramidate compound |
| WO2015066370A1 (en) * | 2013-11-01 | 2015-05-07 | Idenix Pharmaceuticals, Inc. | D-alanine phosphoramidate pronucleotides of 2'-methyl 2'-fluoro guanosine nucleoside compounds for the treatment of hcv |
| CN106554382A (en) * | 2015-09-29 | 2017-04-05 | 四川科伦药物研究院有限公司 | Application in nucleoside phosphoramidite class compound and preparation method thereof and medicine |
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| CN104231023A (en) * | 2013-06-06 | 2014-12-24 | 南京圣和药业有限公司 | Tricyclic fused-heterocyclic nucleoside phosphoramidate compound and preparation method and applications of tricyclic fused-heterocyclic nucleoside phosphoramidate compound |
| WO2015066370A1 (en) * | 2013-11-01 | 2015-05-07 | Idenix Pharmaceuticals, Inc. | D-alanine phosphoramidate pronucleotides of 2'-methyl 2'-fluoro guanosine nucleoside compounds for the treatment of hcv |
| CN104130302A (en) * | 2014-08-08 | 2014-11-05 | 广东东阳光药业有限公司 | Crystal form of nucleotide medicines and preparation method of crystal form |
| CN106554382A (en) * | 2015-09-29 | 2017-04-05 | 四川科伦药物研究院有限公司 | Application in nucleoside phosphoramidite class compound and preparation method thereof and medicine |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113058076A (en) * | 2021-03-29 | 2021-07-02 | 四川大学 | Supermolecule nucleoside hydrogel and preparation method and application thereof |
| CN113058076B (en) * | 2021-03-29 | 2022-03-11 | 四川大学 | Supermolecule nucleoside hydrogel and preparation method and application thereof |
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