CN104829673B - A kind of preparation method of rope fluorine cloth Wei crystal formation 6 - Google Patents
A kind of preparation method of rope fluorine cloth Wei crystal formation 6 Download PDFInfo
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- CN104829673B CN104829673B CN201510234375.9A CN201510234375A CN104829673B CN 104829673 B CN104829673 B CN 104829673B CN 201510234375 A CN201510234375 A CN 201510234375A CN 104829673 B CN104829673 B CN 104829673B
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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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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Abstract
The invention discloses a kind of new method for crystallising for being used to prepare rope fluorine cloth Wei (sofosbuvir) crystal formation 6.Compared with the preparation method of original crystal formation 6, crystallization processes of the invention are by the way that by rope fluorine cloth Wei, from the solution of a variety of organic mixed solvents prepared by cooling crystallization, and good with refining effect, product is easily dried, the advantages of environmental protection.
Description
Technical field
The invention belongs to pharmaceutical technology field, more specifically to a kind of preparation side of novel rope fluorine cloth Wei crystal formation 6
Method.
Background technology
Rope fluorine cloth Wei (sofosbuvir), chemical entitled isopropyl (2S) -2- [[[(2R, 3R, 4R, 5R) -5- (2,4- bis-
Oxygen pyrimidine -1- bases) the fluoro- 3- hydroxy-4-methyls of -4--tetrahydrofuran -2- bases]-Difluoro-phenoxy-phosphoryl] amino] propionic acid
Ester, CAS numberings are 1190307-88-0, and chemical structural formula is as follows：
Rope fluorine cloth Wei is a kind of NS5B polymerases suppression developed by Gilid Science Co. of the U.S. (Glead Sciences)
Preparation, it can block the species specificity required for hepatitis c viral replication individually or when being used in combination with other medicines
Protein, so that the treatment for hepatitis C.Rope fluorine cloth Wei is in December, 2013 by food and medicine Surveillance Authority of the U.S. batch
Quasi- listing, trade name Sovaldi (400 milligrams of formulations).Rope fluorine cloth Wei is first granted orally controlled entirely available for hepatitis C
The medicine for the treatment of, when being treated for specific gene type chronic hepatitis C, can be eliminated to conventional injection interfering effects of drug plain (IFN)
Demand, its global marketing volume in 2014 is more than 10,000,000,000 dollars, with wide market prospects.In November, 2014, U.S.'s food medicine
Product Surveillance Authority have approved containing 400 milligrams of rope fluorine cloth Weis and 90 milligrams of Ledipasvir (another NS5B polymerases suppressions again
Preparation) compound medicine Harvoni, the therapeutic effect of its hepatitis C is more excellent, and market prospects are more wide.
Polymorph in pharmaceuticals is the phenomenon of generally existing in solid drugs, the physicochemical property of different crystal forms medicine difference.
In to solid drugs raw material and formulation process, crystal formation problem is considered as.Be currently known rope fluorine cloth Wei exist polymorphic show
As, and in using rope fluorine cloth Wei as the listing finished medicines of principle active component, used crystal formation is crystal formation 6.
Patent CN102858790A discloses 6 kinds of crystal formations of rope fluorine cloth Wei and preparation method thereof.And United States Patent (USP)
US8618076 introduces and protected the preparation method of crystal formation 6.
Crystal formation 1, its powder x-ray diffraction characteristic peak is 5.2 °, 7.5 °, 9.6 °, 16.7 °, 18.3 °, 22.2 °.Crystal formation 1 can
To be transformed by crystal formation 2, crystal formation 3, crystal formation 4, crystal formation 5.The hygroscopicity of crystal formation 1 itself is stronger, is easily transformed into open-top receptacle
Spawn is converted into crystal formation 6.
Crystal formation 2 be dichloromethane solvate crystallization, its powder x-ray diffraction characteristic peak be 4.9 °, 6.9 °, 9.8 °,
19.8°、20.6°、24.7°、26.1.Crystal formation 2 is crystallized from dichloromethane and obtained, and crystal formation 1 is converted into when drying.
Crystal formation 3 be chloroform crystalline solvate, its powder x-ray diffraction characteristic peak be 6.9 °, 9.8 °, 19.7 °,
20.6°、24.6°.Crystal formation 3 is crystallized from chloroform and obtained, and crystal formation 1 is converted into when drying.
Crystal formation 4, its powder x-ray diffraction characteristic peak is 5.0 °, 6.8 °, 19.9 °, 20.6 °, 24.6 °.Crystal formation 4 is from acetonitrile
Middle crystallization is obtained, and property is unstable, and crystal formation 1 is converted into when being separated by filtration.
Crystal formation 5, its powder x-ray diffraction characteristic peak is 5.2 °, 6.6 °, 7.1 °, 15.7 °, 19.1 °, 25.0 °.Crystal formation 5 from
Crystallization is obtained in methyl phenyl ethers anisole, and property is unstable, and crystal formation 1 is converted into when being separated by filtration.
Crystal formation 6, its powder x-ray diffraction characteristic peak be 6.1 °, 8.2 °, 10.4 °, 12.7 °, 17.2 °, 17.7 °, 18.0 °,
18.8°、19.4°、19.8°、20.1°、20.8°。
Patent US8618076 discloses the following two kinds methods for preparing crystal formation 6, is obtained from the conversion of crystal formation 1：
Method 1：Gelling material was formed by several days under the powder of crystal formation 1 humidity disposed within, by gelling material grind into powder.
This powder is placed in open containers after 6~10 weeks to sample slowly becomes crystal formation 6.
Method 2：It will add in the water of 5~50 mg/mls, stirred at normal temperature or 50 DEG C, crystal formation 1 under the normal temperature of crystal formation 1
Crystal formation 6 is converted within a few hours.
And patent CN102858790A and US8618076 are specialized, and crystal formation 6 can not be obtained from organic solvent.
However, there is larger problem in the preparation method of above-mentioned rope fluorine cloth Wei crystal formation 6.
First, the preparation method of two kinds of rope fluorine cloth Wei crystal formations 6 is transformed from crystal formation 1.And crystal formation 1 is inherently more difficult
Prepare, it is necessary to pass through other transformation of crystal.There is very big waste in this, less efficient in technique.
Secondly, the more difficult control of technical process of the preparation method of two kinds of rope fluorine cloth Wei crystal formations 6.The step of method 1, is tediously long, bag
Include to form the slowly varying of jello, grinding and 6~10 weeks, therefore do not possess the feasibility of reality production；Method 2 is related in water
In the conversion of heterogeneous states of matter, process is difficult to control to, and is difficult that the condition provided according to document is reappeared.
3rd, the existing preparation method refined product relatively difficult to achieve of two kinds of rope fluorine cloth Wei crystal formations 6, deimpurity purpose is gone,
Therefore it is accomplished by strictly controlling the chemical purity of product in raw material link.This significantly increases process costs.
4th, the technique converted in existing use water can produce a large amount of impure waste water, post processing and reclaim difficult.
In summary, in the urgent need to a kind of new rope fluorine cloth Wei crystallization processes to solve the disadvantage mentioned above of existing process, energy
Enough simple efficient contexts produce rope fluorine cloth Wei crystal formation 6 with open arms.
The content of the invention
Goal of the invention：To solve problems of the prior art, the present invention provides a kind of novel rope fluorine cloth Wei crystal formation 6
Preparation method, the crystallization processes are simply efficient, and favorable repeatability, environmental protection efficiently solves existing crystal formation and its system
The deficiency of Preparation Method.
Technical scheme：To realize above-mentioned technical purpose, the present invention proposes the preparation side for obtaining rope fluorine cloth Wei crystal formation 6
Method, comprises the following steps：
(1) rope fluorine cloth Wei is dissolved in solvent and obtains rope fluorine cloth Wei solution, wherein, the solvent is cyclopentyl methyl ether or ring
The mixture of amyl group methyl ether and other ether solvents；
(2) the rope fluorine cloth Wei solution is subjected to crystallization；
(3) drying process will be carried out after the solid filtering obtained by crystallization, elution.
Preferably, the content of cyclopentyl methyl ether accounts for 60~100wt% in the solvent.
Preferably, other described ether solvents are any one in isopropyl ether, butyl oxide, methyl phenyl ethers anisole and benzyl ether or many
The mixture planted.
Preferably, in described rope fluorine cloth Wei solution, the volume mass ratio of solvent and rope fluorine cloth Wei is 5 mls/g~50
Ml/g.It is further preferable that in described rope fluorine cloth Wei solution, the volume mass ratio of solvent and rope fluorine cloth Wei is 8 mls/g
~20 mls/g.
Wherein, in the step of crystallization, the rope fluorine cloth Wei solution, which is reached by being heated to 70 DEG C~95 DEG C, to be completely dissolved,
Then crystallization is carried out by cooling, recrystallization temperature is 0~25 DEG C.The purpose of heating for dissolving is to allow rope fluorine cloth Wei to be completely dissolved simultaneously
Eliminate the influence of the nucleus of other a small amount of crystal formations that may be present.
Preferably, in step (2), rope fluorine cloth Wei solution crystallization under standing or stirring condition, suitable stirring speed
Rate is 0~100 rev/min.
Preferably, the speed of the cooling is 0.5~10 DEG C/min.
Preferably, in step (3), when eluting the solid being filtrated to get, the solvent that the elution is used is isopropyl ether or different
The mixture of propyl ether and other organic solvents, the wherein content of isopropyl ether are 80~100wt% (i.e. mass percent).
Beneficial effect：Rope fluorine cloth Wei is crystallized by substantial amounts of experiment and optimization and obtains crystalline substance by the present invention from organic solvent
Type 6, realizes rope fluorine cloth Wei crude product being converted into from the solution of organic solvent and has good stability, is suitable for use as medicine system
The product of crystal formation 6 of agent, eliminates the complicated step of converting between the crystal in original preparation method of crystal formation 6.The system of the present invention
Preparation Method realizes the purification to rope fluorine cloth Wei and refined while rope fluorine cloth Wei single crystal form 6 are obtained, can be from amorphous
The step of rope fluorine cloth Wei crude product one obtain the high-purity raw medicine product of high purity more than 99.5%, meanwhile, crystallization of the invention
Technique is simply efficient, favorable repeatability, efficiently solves the deficiency of the existing preparation method of rope fluorine cloth Wei crystal formation 6.
Brief description of the drawings
Fig. 1 is the X-ray powder diffraction figure of the product obtained according to embodiments of the invention 1；
Fig. 2 is to be schemed according to the TGA of the rope fluorine cloth Wei product of embodiments of the invention 1；
Fig. 3 is to be schemed according to the DSC of the rope fluorine cloth Wei product of embodiments of the invention 1；
Fig. 4 is to be schemed according to the HPLC of the rope fluorine cloth Wei product of embodiments of the invention 6.
Embodiment
With reference to embodiment, the present invention will be described in more detail, but does not therefore limit the present invention to described
Within scope of embodiments.The experimental method of unreceipted actual conditions is conventionally carried out with condition in the following example.
Heretofore described room temperature refers to 10 DEG C~30 DEG C.
In the preparation method of the crystal formation 6 of the present invention, rope fluorine cloth Wei Jun uses prepared by the method reported by existing literature
Rope fluorine cloth Wei product (such as J.Med.Chem.2010,53,7202-7218)；Other solvents and reagent using commercially available chemistry it is pure or
Analyze net product.
X-ray powder diffraction instrument device used in the embodiment of the present invention is that PANalytical companies X ' pert PRO types X is penetrated
Line powder diffractometer.Using Cu-K alpha rays, measured power is 40kV × 250mA, and sweep speed is 5 °/minute, scanning range 4
The θ of the θ of~80 ° (2 θ)~2 is continuously scanned.The embodiment of the present invention is obtained in X-ray powder diffraction figure, and transverse axis is diffraction maximum 2 θ
Put (unit：Degree)；The longitudinal axis is diffraction peak intensity.
Differential scanning amount hot-hot weight (DSC-TGA) analysis determining instrument is Mettler used in the embodiment of the present invention
The type synchronous solvings of TGA/DSC 1 of Toledo companies.Measurement range is 25~350 DEG C, and programming rate is 10 DEG C/min,
Protected using nitrogen.The embodiment of the present invention is obtained in differential scanning amount hot-hot weight (DSC-TGA) figure, thermogravimetric (TGA) figure and amount
Hot (DSC) figure is to represent side by side up and down.Transverse axis is temperature (DEG C) wherein in thermal multigraph, and the longitudinal axis is quality (milligram), in calorimetric figure
Transverse axis is temperature (unit：DEG C), the longitudinal axis is power (unit：Milliwatt).
The present invention determines the HPLC methods of product purity：HPLC column be Agilent ZORBAX SB-C18,4.6*150mm,
3.5um, 35 DEG C of column temperature；Mobile phase A：0.1% phosphate aqueous solution (containing 10 mM/ls of Potassium Hexafluorophosphates)；B：Acetonitrile
Embodiment 1
1.0 grams of rope fluorine cloth Weis are mixed with 10.0 milliliters of cyclopentyl methyl ethers and 1.0 milliliters of methyl phenyl ethers anisoles, this mixture are heated extremely
75 ± 3 DEG C and under 20 revs/min stirring be completely dissolved solid, be then cooled in 90 minutes 10 ± 3 DEG C and herein temperature
Degree is lower to stand 48 hours, takes out the white powder crystal separated out by filtering, dries and obtain after being washed with 3 milliliters of isopropyl ethers
0.92 gram of product.
Powder x-ray diffraction analysis are carried out to the crystal prototype of acquisition, its result is as shown in Figure 1.It is corresponding with Fig. 1, rope
The powder x-ray diffraction data of fluorine cloth Wei crystal formation 6 are as shown in table 1.
The pXRD characteristic peak positions of the product of 1 embodiment of table 1
Means of differential scanning calorimetry-thermogravimetric analysis is carried out to the powder sample, its result is as shown in Figure 2.Shown pXRD, DSC-
The test results such as TGA are identical with document report rope fluorine cloth Wei 6 feature spectrograms of crystal formation, it was demonstrated that product is rope fluorine cloth Wei crystal formation 6.
Embodiment 2
1.0 grams of rope fluorine cloth Weis are mixed with 10.0 milliliters of cyclopentyl methyl ethers and 2.0 milliliters of benzyl ether, this mixture are heated extremely
75 ± 3 DEG C and under 20 revs/min stirring be completely dissolved solid, 5 ± 3 DEG C were then cooled in 90 minutes and in this temperature
Lower stirring 48 hours, the white powder crystal separated out is taken out by filtering, and drying obtains 0.93 after being washed with 3 milliliters of isopropyl ethers
Gram product, yield is 93%.The test such as pXRD, DSC-TGA will be carried out after product grinding, with document report rope fluorine cloth Wei Jing
The feature spectrogram of type 6 is identical, it was demonstrated that product is rope fluorine cloth Wei crystal formation 6.
Embodiment 3
1.0 grams of rope fluorine cloth Weis are mixed with 10.0 milliliters of cyclopentyl methyl ethers and 2.0 milliliters of butyl oxides, this mixture are heated extremely
85 ± 3 DEG C and under 40 revs/min stirring be completely dissolved solid, be then cooled in 90 minutes 15 ± 3 DEG C and herein temperature
The lower stirring of degree 48 hours, takes out the white powder crystal separated out by filtering, dries and obtain after being washed with 3 milliliters of isopropyl ethers
0.93 gram of product, yield is 93%.
The test such as pXRD, DSC-TGA will be carried out after product grinding, with the characteristic spectrum of document report rope fluorine cloth Wei crystal formation 6
Figure is identical, it was demonstrated that product is rope fluorine cloth Wei crystal formation 6.
Embodiment 4
0.5 gram of rope fluorine cloth Wei is mixed with 5 milliliters of cyclopentyl methyl ethers, 0.5 milliliter of isopropyl ether and 0.5 milliliter of benzyl ether, plus
This hot mixture to 80 ± 3 DEG C and is completely dissolved solid in stirring under 50 revs/min, is then cooled to 5 ± 3 in 30 minutes
DEG C and at this temperature stand 48 hours, by filter take out separate out solid, elute with isopropyl ether and dries obtain white powder
Last shape crystallization.
The test such as pXRD, DSC-TGA will be carried out after product grinding, with the characteristic spectrum of document report rope fluorine cloth Wei crystal formation 6
Figure is identical, it was demonstrated that product is rope fluorine cloth Wei crystal formation 6.
Embodiment 5
0.5 gram of rope fluorine cloth Wei is mixed with 5 milliliters of cyclopentyl methyl ethers, this mixture is heated to 80 ± 3 DEG C and in 50 revs/min
Stirring is completely dissolved solid under clock, and 5 ± 3 DEG C were then cooled in 30 minutes and 48 hours are stood at this temperature, passed through
The solid separated out is taken out in filtering, is eluted with isopropyl ether and dries acquisition white, needle-shaped crystals.
The test such as pXRD, DSC-TGA will be carried out after product grinding, with the characteristic spectrum of document report rope fluorine cloth Wei crystal formation 6
Figure is identical, it was demonstrated that product is rope fluorine cloth Wei crystal formation 6.
Embodiment 6
By 50 grams of rope fluorine cloth Weis (amorphous crude product, purity be 95.0%) with 500 milliliters of cyclopentyl methyl ethers and 50 milliliters of benzene
Methyl ether is mixed, and is heated this mixture to 85 ± 3 DEG C and is completely dissolved solid in stirring under 20 revs/min, then at 90 minutes
Inside it is cooled to 20 ± 3 DEG C and adds 0.2 gram of 6 powder of rope fluorine cloth Wei crystal formation as crystal seed, it is small with 30 revs/min of speed stirring 16
When and be cooled to 0 DEG C keep one hour.Crystalline mixture is filtered and eluted twice with isopropyl ether.Filter cake is in 0.3atm, 45 DEG C
Under be dried under reduced pressure, be completely dried after 4 hours and obtain 46.0 grams of white powdery solids, yield is 92.0%, and purity is
99.8%.
The test such as pXRD, DSC-TGA will be carried out after product grinding, with the characteristic spectrum of document report rope fluorine cloth Wei crystal formation 6
Figure is identical, it was demonstrated that product is rope fluorine cloth Wei crystal formation 6.
Embodiment 7
By 50 grams of rope fluorine cloth Weis, (crystal formation 2, purity is 98.9%) to be mixed with 500 milliliters of cyclopentyl methyl ethers and 50 milliliters of isopropyl ethers
Close, heat this mixture to 85 ± 3 DEG C and be completely dissolved solid in stirring under 20 revs/min, then cooled down in 90 minutes
To 20 ± 3 DEG C and 0.2 gram of 6 powder of rope fluorine cloth Wei crystal formation is added as crystal seed, stir 16 hours and drop with 30 revs/min of speed
Warm to 0 DEG C is kept for one hour.Crystalline mixture is filtered and eluted twice with isopropyl ether.Filter cake is depressurized at 0.3atm, 45 DEG C
Dry, be completely dried after 4 hours and obtain 47.5 grams of white powdery solids, yield is 95.0%, and purity is 99.8%.
The test such as pXRD, DSC-TGA will be carried out after product grinding, with the characteristic spectrum of document report rope fluorine cloth Wei crystal formation 6
Figure is identical, it was demonstrated that product is rope fluorine cloth Wei crystal formation 6.
In summary, method of the invention is prepared with prior art (such as J.Med.Chem.2010,53,7202-7218)
Rope fluorine cloth Wei crude product is raw material, is to obtain crystal formation 6 by the simple crystallisation step of a step in organic solvent.The crystal formation can be from
Obtained in a variety of different organic solvent combinations, preparation technology is simple, product is the single crystal form of rope fluorine cloth Wei crystal formation 6, crystal is pure
Spend, stability is high.
Comparative example 1：
Added using the starting material rope fluorine cloth Wei crude product 5 gram (amorphous, purity 95.0%) same with the crystallization process of embodiment 5
Enter in 250 milliliters of water, be heated to 50 DEG C of 0.1 gram of 6 crystal seeds of addition crystal formation and stir.Occur after 120 hours without crystallization.
Comparative example 2：
Crystal formation 1 is prepared from rope fluorine cloth Wei crystal formation 2 by the method for document report, the rope fluorine cloth Wei 5 after refining is used
Gram (crystal formation 1, purity 99.0%) is added in 200 milliliters of water as initiation material, is stirred and is heated to 50 DEG C.Crystallization is only adding
Plus rope fluorine cloth Wei crystal formation 6 (white powder, 0.1 gram) occurs as after crystal seed.It is cold in 90 minutes after being stirred 1 hour at 50 DEG C
But to 20 DEG C and keep 16 hours, be cooled to afterwards in 30 minutes 0~5 DEG C and keep 2.5 hours, filtering for crystallizing mixture is obtained
To filter cake and with 50 milliliters of water washings, filter cake is dried under reduced pressure at 0.3atm, 45 DEG C, is just completely dried, is obtained after 48 hours
4.3 grams of products, yield is 86%.
PXRD and fusing point, determine product for rope fluorine cloth Wei crystal formation 6 after measured.It is 98.9% to determine product purity through HPLC,
Its purity and major impurity content are compared with before crystallization without significant changes.
Table 2 compared for one of prior art (i.e. the method for comparative example 1 and comparative example 2) and the present invention in terms of preparation technology
The contrast of a little distinguishing features.
It can be drawn from the result of table 2, the preparation method that this patent is disclosed realizes rope fluorine cloth Wei is amorphous thick
Product from the solution of organic solvent to stable crystal form direct transformation, eliminate between the crystal in original preparation method of crystal formation 6
Step of converting.The preparation method of the present invention realizes and rope fluorine cloth Wei is carried while rope fluorine cloth Wei single crystal form 6 are obtained
It is pure and mild refined, the high-purity raw medicine production of high purity more than 99.5% can be obtained from the unbodied step of rope fluorine cloth Wei crude product one
Product, meanwhile, crystallization processes of the invention are simply efficient, favorable repeatability, efficiently solve the existing preparation of rope fluorine cloth Wei crystal formation 6
The deficiency of method.
Existing technology of preparing and the inventive method table of comparisons of 2 rope fluorine cloth Wei crystal formation of table 6
Claims (6)
1. a kind of preparation method of rope fluorine cloth Wei crystal formation 6, the powder x-ray diffraction characteristic peak of crystal formation 6 is 6.1 °, 8.2 °,
10.4 °, 12.7 °, 17.2 °, 17.7 °, 18.0 °, 18.8 °, 19.4 °, 19.8 °, 20.1 °, 20.8 °, it is characterised in that including under
Row step：
(1) rope fluorine cloth Wei is dissolved in solvent and obtains rope fluorine cloth Wei solution, wherein, the solvent is cyclopentyl methyl ether or cyclopenta
The mixture of methyl ether and other ether solvents；
(2) the rope fluorine cloth Wei solution is subjected to crystallization；
(3) drying process will be carried out after the solid filtering obtained by crystallization, elution；
Wherein, then the rope fluorine cloth Wei solution analysed by being heated to 70 DEG C~95 DEG C up to being completely dissolved by cooling
Crystalline substance, recrystallization temperature is 0~25 DEG C；The rate of temperature fall of the cooling is 0.5~10 DEG C/min.
2. preparation method according to claim 1, it is characterised in that in the solvent content of cyclopentyl methyl ether account for 60~
100wt%.
3. preparation method according to claim 1, it is characterised in that other described ether solvents be isopropyl ether, butyl oxide,
The mixture of any one or more in methyl phenyl ethers anisole and benzyl ether.
4. preparation method according to claim 1, it is characterised in that in described rope fluorine cloth Wei solution, solvent and rope fluorine
The volume mass ratio of cloth Wei is 5 mls/g~50 mls/g.
5. preparation method according to claim 1, it is characterised in that in step (2), the rope fluorine cloth Wei solution is being stood
Or crystallization under stirring condition, stir speed (S.S.) is 0~100 rev/min.
6. preparation method according to claim 1, it is characterised in that in step (3), when eluting the solid being filtrated to get,
Used solvent is the content of isopropyl ether or isopropyl ether and the mixture, wherein isopropyl ether of any one or more organic solvent
Account for 80~100wt%.
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| CN106083963A (en) * | 2016-06-08 | 2016-11-09 | 上海现代制药海门有限公司 | A kind of preparation method of Suo Feibuwei crystal formation 6 |
| CN108727439A (en) * | 2018-08-07 | 2018-11-02 | 浙江华纳药业有限公司 | A kind of preparation method of VI crystal forms of Suo Feibuwei |
| CN109369757B (en) * | 2018-11-12 | 2020-12-29 | 浙江外国语学院 | Method for preparing Sofosbuvir crystal form 6 |
| CN111233956B (en) * | 2018-11-29 | 2023-04-28 | 北京凯因科技股份有限公司 | Crystal form of sofosbuvir and preparation method thereof |
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| CN104277088A (en) * | 2014-10-29 | 2015-01-14 | 汤律进 | Sofosbuvir monocrystal M and preparation method and applications of sofosbuvir monocrystal M |
| CN104447924A (en) * | 2014-11-07 | 2015-03-25 | 南京旗昌医药科技有限公司 | Crystal forms of sofosbuvir and preparation method of crystal forms |
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