CN104829673A - Preparation method of sofosbuvir crystal form 6 - Google Patents
Preparation method of sofosbuvir crystal form 6 Download PDFInfo
- Publication number
- CN104829673A CN104829673A CN201510234375.9A CN201510234375A CN104829673A CN 104829673 A CN104829673 A CN 104829673A CN 201510234375 A CN201510234375 A CN 201510234375A CN 104829673 A CN104829673 A CN 104829673A
- Authority
- CN
- China
- Prior art keywords
- fluorine cloth
- rope fluorine
- cloth wei
- preparation
- crystal formation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a novel crystallization method for preparing a sofosbuvir crystal form 6. Compared with an original preparation method of the crystal form 6, the novel crystallization method disclosed by the invention has the advantages that the purification effect is good, products are easy to dry, an environment-friendly effect is achieved and the like since sofosbuvir is prepared from a solution containing various organic mixed solvents through cooling crystallization.
Description
Technical field
The invention belongs to medical art, more particularly, relate to a kind of preparation method of rope fluorine cloth Wei crystal formation 6 of novelty.
Background technology
Rope fluorine cloth Wei (sofosbuvir); chemistry sec.-propyl (2S)-2-[[[(2R by name; 3R; 4R; 5R)-5-(2; 4-dioxypyrimidine-1-base)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran (THF)-2-base]-Difluoro-phenoxy-phosphoryl] amino] propionic ester, CAS is numbered 1190307-88-0, and chemical structural formula is as follows:
Rope fluorine cloth Wei is a kind of NS5B AG14361 developed by Gilid Science Co. of the U.S. (Glead Sciences), it is when separately or with other medicines conbined usage, a species-specific proteins required for hepatitis c viral replication capable of blocking, thus for the treatment of hepatitis C.Rope fluorine cloth Wei ratifies listing in December, 2013 by U.S. food Drug Administration, and commodity are called Sovaldi (400 milligrams of formulations).Rope fluorine cloth Wei is the first granted medicine that can be used for the full oral administration of hepatitis C, when treating for specific gene type chronic hepatitis C, the demand to conventional injection interfering effects of drug element (IFN) can be eliminated, its global marketing volume in 2014, more than 10,000,000,000 dollars, has wide market outlook.In November, 2014, U.S. food Drug Administration have approved again the compound medicine Harvoni containing 400 milligrams of rope fluorine cloth Weis and 90 milligrams of Ledipasvir (another kind of NS5B AG14361), the result for the treatment of of its hepatitis C is more excellent, and market outlook are more wide.
Polymorph in pharmaceuticals is ubiquitous phenomenon in solid pharmaceutical, the physico-chemical property difference to some extent of different crystal forms medicine.To in solid pharmaceutical raw material and formulation process, crystal formation problem should be considered.There is polymorphism in current known rope fluorine cloth Wei, and in the listing finished medicines being principle active component with rope fluorine cloth Wei, the crystal formation used is crystal formation 6.
Patent CN102858790A discloses 6 kinds of crystal formations of rope fluorine cloth Wei and preparation method thereof.And US Patent No. 8618076 introduces and protects 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 be transformed by crystal formation 2, crystal formation 3, crystal formation 4, crystalline form of 5.The water absorbability of crystal formation 1 own is comparatively strong, is easily transformed into spawn or is converted into crystal formation 6 in open container.
Crystal formation 2 is dichloromethane solvate crystallization, and its powder x-ray diffraction characteristic peak is 4.9 °, 6.9 °, 9.8 °, 19.8 °, 20.6 °, 24.7 °, 26.1.Crystal formation 2 crystallization from methylene dichloride obtains, and is converted into crystal formation 1 time dry.
Crystal formation 3 is trichloromethane crystalline solvate, and its powder x-ray diffraction characteristic peak is 6.9 °, 9.8 °, 19.7 °, 20.6 °, 24.6 °.Crystal formation 3 crystallization from trichloromethane obtains, and is converted into crystal formation 1 time dry.
Crystal formation 4, its powder x-ray diffraction characteristic peak is 5.0 °, 6.8 °, 19.9 °, 20.6 °, 24.6 °.Crystal formation 4 crystallization from acetonitrile obtains, and character is unstable, is converted into crystal formation 1 during filtering separation.
Crystalline form of 5, its powder x-ray diffraction characteristic peak is 5.2 °, 6.6 °, 7.1 °, 15.7 °, 19.1 °, 25.0 °.Crystalline form of 5 crystallization from methyl-phenoxide obtains, and character is unstable, is converted into crystal formation 1 during filtering separation.
Crystal formation 6, its powder x-ray diffraction characteristic peak 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 °.
Patent US8618076 discloses following two kinds of methods preparing crystal formation 6, is all to transform from crystal formation 1 to obtain:
Method 1: form gelling material, by gelling material grind into powder in several days under crystal formation 1 powder being placed in indoor humidity.After this powder is placed in open containers 6 ~ 10 week, sample slowly becomes crystal formation 6.
Method 2: add in the water of 5 ~ 50 mg/ml by under crystal formation 1 normal temperature, stir at normal temperature or 50 DEG C, crystal formation 1 is converted into crystal formation 6 within a few hours.
And patent CN102858790A and US8618076 all specializes, crystal formation 6 cannot be obtained from organic solvent.
But all 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 inherently more difficult preparation, need by other transformation of crystals.There is very large waste in this, efficiency is lower in technique.
Secondly, the more difficult control of technological process of the preparation method of two kinds of rope fluorine cloth Wei crystal formations 6.The step of method 1 is tediously long, comprises and forms jello, grinding and the slow change in 6 ~ 10 weeks, therefore does not possess the feasibility of reality production; The heterogeneous states of matter that method 2 relates in water transforms, and process is difficult to control, and the condition being difficult to provide according to document is reappeared.
3rd, the existing preparation method of two kinds of rope fluorine cloth Wei crystal formations 6 is more difficult realizes refined product, go deimpurity object, therefore strictly controls the chemical purity of product with regard to needing in raw material link.This significantly increases process costs.
4th, the technique transformed in existing use water can produce a large amount of impure waste water, aftertreatment and recovery difficulty.
In sum, in the urgent need to a kind of new rope fluorine cloth Wei crystallization processes to solve the above shortcoming of existing technique, simply efficient context rope fluorine cloth Wei crystal formation 6 can be produced with open arms.
Summary of the invention
Goal of the invention: for solving problems of the prior art, the invention provides a kind of preparation method of rope fluorine cloth Wei crystal formation 6 of novelty, this crystallization processes is simply efficient, favorable repeatability, environmental protection, efficiently solves the deficiency of existing crystal formation and preparation method thereof.
Technical scheme: for realizing above-mentioned technical purpose, the present invention proposes the preparation method for obtaining rope fluorine cloth Wei crystal formation 6, comprising the following steps:
(1) be dissolved in solvent by rope fluorine cloth Wei and obtain rope fluorine cloth Wei solution, wherein, described solvent is the mixture of cyclopentyl methyl ether or cyclopentyl methyl ether and other ether solvents;
(2) described rope fluorine cloth Wei solution is carried out crystallization;
(3) drying treatment is carried out after the solid filtering obtained by crystallization, drip washing.
Preferably, in described solvent, the content of cyclopentyl methyl ether accounts for 60 ~ 100wt%.
Preferably, other ether solvents described are any one or the multiple mixture in isopropyl ether, dibutyl ether, methyl-phenoxide and dibenzyl ether.
Preferably, in described rope fluorine cloth Wei solution, the volume mass ratio of solvent and rope fluorine cloth Wei is 5 mls/g ~ 50 mls/g.More preferably, 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, described rope fluorine cloth Wei solution reaches dissolve completely by being heated to 70 DEG C ~ 95 DEG C, and then carry out crystallization by cooling, recrystallization temperature is 0 ~ 25 DEG C.Heating for dissolving object be the impact allowing the complete CL of rope fluorine cloth Wei also eliminate the nucleus of other crystal formations a small amount of that may exist.
Preferably, in step (2), described rope fluorine cloth Wei solution is leaving standstill or crystallization under agitation condition, and suitable stir speed (S.S.) is 0 ~ 100 rev/min.
Preferably, the speed of described cooling is 0.5 ~ 10 DEG C/min.
Preferably, in step (3), when the solid obtained is filtered in drip washing, the mixture that the solvent that described drip washing uses is isopropyl ether or isopropyl ether and other organic solvents, wherein the content of isopropyl ether is 80 ~ 100wt% (i.e. mass percent).
Beneficial effect: the present invention is by a large amount of experiments and optimization, the crystallization from organic solvent of rope fluorine cloth Wei is obtained crystal formation 6, achieve crystal formation 6 product rope fluorine cloth Wei crude product being converted into from the solution of organic solvent the pharmaceutical preparation that has good stability, is suitable for use as, eliminate the complicated step of converting between the crystal in original crystal formation 6 preparation method.Preparation method of the present invention is while acquisition rope fluorine cloth Wei single crystal form 6, achieve the purification of rope fluorine cloth Wei and refining, the high-purity raw medicine product of high purity more than 99.5% can be obtained from unbodied rope fluorine cloth Wei crude product one step, simultaneously, crystallization processes of the present invention is simply efficient, favorable repeatability, efficiently solves the deficiency of the existing preparation method of rope fluorine cloth Wei crystal formation 6.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction figure of the product obtained according to embodiments of the invention 1;
Fig. 2 schemes according to the TGA of the rope fluorine cloth Wei product of embodiments of the invention 1;
Fig. 3 schemes according to the DSC of the rope fluorine cloth Wei product of embodiments of the invention 1;
Fig. 4 schemes according to the HPLC of the rope fluorine cloth Wei product of embodiments of the invention 6.
Embodiment
Below in conjunction with embodiment, the present invention will be described in more detail, but therefore do not limit the present invention within described scope of embodiments.In the following example, the experimental technique of unreceipted actual conditions all conventionally carries out with condition.
Room temperature described in the present invention refers to 10 DEG C ~ 30 DEG C.
In the preparation method of crystal formation 6 of the present invention, rope fluorine cloth Wei Jun uses rope fluorine cloth Wei product (as J.Med.Chem.2010,53,7202-7218) prepared by the method for existing bibliographical information; Other solvents and reagent all use commercially available chemical pure or analytical pure product.
The x-ray powder diffraction instrument device that the embodiment of the present invention uses is PANalytical company X ' pert PRO type x-ray powder diffraction instrument.Adopt Cu-K alpha-ray, measured power is 40kV × 250mA, and sweep velocity is 5 °/minute, the θ ~ 2 θ continuous sweep of sweep limit 4 ~ 80 ° (2 θ).The embodiment of the present invention obtains in X-ray powder diffraction figure, and transverse axis is diffraction peak 2 θ position (unit: degree); The longitudinal axis is diffraction peak intensity.
Differential scanning calorimetric-thermogravimetric (DSC-TGA) that the embodiment of the present invention uses analyzes the TGA/DSC 1 type synchronous solving that determining instrument is Mettler Toledo company.Useful range is 25 ~ 350 DEG C, and heat-up rate is 10 DEG C/min, adopts nitrogen protection.In differential that the embodiment of the present invention obtains scanning calorimetric-thermogravimetric (DSC-TGA) figure, thermogravimetric (TGA) figure and calorimetric (DSC) figure represents up and down side by side.Wherein in thermal multigraph, transverse axis is temperature (DEG C), and the longitudinal axis is quality (milligram), and in calorimetric figure, transverse axis is temperature (unit: DEG C), and the longitudinal axis is power (unit: milliwatt).
The present invention measures the HPLC method of product purity: HPLC column is Agilent ZORBAX SB-C18,4.6*150mm, 3.5um, column temperature 35 DEG C; 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 ether and 1.0 milliliters of methyl-phenoxides, heating this mixture to 75 ± 3 DEG C and stirring under 20 revs/min makes solid dissolve completely, then in 90 minutes, be cooled to 10 ± 3 DEG C and leave standstill 48 hours at this temperature, by filtering the white powder crystal taking out and separate out, obtain 0.92 gram of product by 3 milliliters of isopropyl ether washing post-dryings.
Carry out powder x-ray diffraction analysis to the crystal prototype obtained, its result as shown in Figure 1.Corresponding with Fig. 1, the powder x-ray diffraction data of rope fluorine cloth Wei crystal formation 6 are as shown in table 1.
The pXRD characteristic peak positions of table 1 embodiment 1 product
Carry out means of differential scanning calorimetry-thermogravimetric analysis to this powdered sample, its result as shown in Figure 2.The test results such as shown pXRD, DSC-TGA are all identical with bibliographical information rope fluorine cloth Wei crystal formation 6 feature spectrogram, confirm 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 ether and 2.0 milliliters of dibenzyl ether, heating this mixture to 75 ± 3 DEG C and stirring under 20 revs/min makes solid dissolve completely, then in 90 minutes, be cooled to 5 ± 3 DEG C and stir 48 hours at this temperature, by filtering the white powder crystal taking out and separate out, obtain 0.93 gram of product by 3 milliliters of isopropyl ether washing post-dryings, productive rate is 93%.The tests such as pXRD, DSC-TGA are carried out by after product grinding, all identical with bibliographical information rope fluorine cloth Wei crystal formation 6 feature spectrogram, confirm 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 ether and 2.0 milliliters of dibutyl ethers, heating this mixture to 85 ± 3 DEG C and stirring under 40 revs/min makes solid dissolve completely, then in 90 minutes, be cooled to 15 ± 3 DEG C and stir 48 hours at this temperature, by filtering the white powder crystal taking out and separate out, obtain 0.93 gram of product by 3 milliliters of isopropyl ether washing post-dryings, productive rate is 93%.
The tests such as pXRD, DSC-TGA are carried out by after product grinding, all identical with bibliographical information rope fluorine cloth Wei crystal formation 6 feature spectrogram, confirm 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 ether, 0.5 milliliter of isopropyl ether and 0.5 milliliter of dibenzyl ether, heating this mixture to 80 ± 3 DEG C and stirring under 50 revs/min makes solid dissolve completely, then in 30 minutes, be cooled to 5 ± 3 DEG C and leave standstill 48 hours at this temperature, by filtering the solid taking out and separate out, obtain white powder crystallization with isopropyl ether drip washing is also dry.
The tests such as pXRD, DSC-TGA are carried out by after product grinding, all identical with bibliographical information rope fluorine cloth Wei crystal formation 6 feature spectrogram, confirm 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 ether, heating this mixture to 80 ± 3 DEG C and stirring under 50 revs/min makes solid dissolve completely, then in 30 minutes, be cooled to 5 ± 3 DEG C and leave standstill 48 hours at this temperature, by filtering the solid taking out and separate out, obtain white, needle-shaped crystals with isopropyl ether drip washing is also dry.
The tests such as pXRD, DSC-TGA are carried out by after product grinding, all identical with bibliographical information rope fluorine cloth Wei crystal formation 6 feature spectrogram, confirm that product is rope fluorine cloth Wei crystal formation 6.
Embodiment 6
By 50 grams of rope fluorine cloth Wei (amorphous crude products, purity is 95.0%) mix with 500 milliliters of cyclopentyl methyl ether and 50 milliliters of methyl-phenoxides, heating this mixture to 85 ± 3 DEG C and stirring under 20 revs/min makes solid dissolve completely, then in 90 minutes, be cooled to 20 ± 3 DEG C and add 0.2 gram, rope fluorine cloth Wei crystal formation 6 powder as crystal seed, stir 16 hours with the speed of 30 revs/min and be cooled to 0 DEG C of maintenance one hour.Crystalline mixture is filtered and uses isopropyl ether drip washing twice.Filter cake is at 0.3atm, and drying under reduced pressure at 45 DEG C, after 4 hours, complete drying obtains white powdery solids 46.0 grams, and productive rate is 92.0%, and purity is 99.8%.
The tests such as pXRD, DSC-TGA are carried out by after product grinding, all identical with bibliographical information rope fluorine cloth Wei crystal formation 6 feature spectrogram, confirm that product is rope fluorine cloth Wei crystal formation 6.
Embodiment 7
By 50 grams of rope fluorine cloth Wei (crystal formations 2, purity is 98.9%) mix with 500 milliliters of cyclopentyl methyl ether and 50 milliliters of isopropyl ethers, heating this mixture to 85 ± 3 DEG C and stirring under 20 revs/min makes solid dissolve completely, then in 90 minutes, be cooled to 20 ± 3 DEG C and add 0.2 gram, rope fluorine cloth Wei crystal formation 6 powder as crystal seed, stir 16 hours with the speed of 30 revs/min and be cooled to 0 DEG C of maintenance one hour.Crystalline mixture is filtered and uses isopropyl ether drip washing twice.Filter cake is at 0.3atm, and drying under reduced pressure at 45 DEG C, after 4 hours, complete drying obtains white powdery solids 47.5 grams, and productive rate is 95.0%, and purity is 99.8%.
The tests such as pXRD, DSC-TGA are carried out by after product grinding, all identical with bibliographical information rope fluorine cloth Wei crystal formation 6 feature spectrogram, confirm that product is rope fluorine cloth Wei crystal formation 6.
In sum, the rope fluorine cloth Wei crude product that method of the present invention is prepared with prior art (as J.Med.Chem.2010,53,7202-7218), for raw material, namely obtains crystal formation 6 through the simple crystallisation step of a step in organic solvent.This crystal formation can obtain from multiple different organic solvent combination, and preparation technology is simple, and product is rope fluorine cloth Wei crystal formation 6 single crystal form, and crystal purity is good, and stability is high.
Comparative example 1:
Use the initiator rope fluorine cloth Wei crude product 5 gram (amorphous, purity 95.0%) same with embodiment 5 crystallisation process to add in 250 ml waters, be heated to 50 DEG C and add crystal formation 6 crystal seed 0.1 gram and stir.Occur without crystallization after 120 hours.
Comparative example 2:
Prepare crystal formation 1 by the method for bibliographical information from rope fluorine cloth Wei crystal formation 2, use the rope fluorine cloth Wei 5 grams (crystal formation 1, purity 99.0%) after refining as starting raw material, to add in 200 ml waters, stir and be heated to 50 DEG C.Crystallization only occurs as after crystal seed in interpolation rope fluorine cloth Wei crystal formation 6 (white powder, 0.1 gram).At 50 DEG C, stirring was cooled to 20 DEG C after 1 hour and keeps 16 hours in 90 minutes, in 30 minutes, be cooled to 0 ~ 5 DEG C afterwards and keep 2.5 hours, filtering for crystallizing mixture obtains filter cake and washs with 50 ml waters, filter cake is at 0.3atm, drying under reduced pressure at 45 DEG C, just complete drying after 48 hours, obtain 4.3 grams of products, productive rate is 86%.
PXRD and fusing point after measured, determines that product is rope fluorine cloth Wei crystal formation 6.Through HPLC measure product purity be 98.9%, its purity and major impurity content compared with before crystallization without noticeable change.
Table 2 compared for the contrast of prior art (i.e. the method for comparative example 1 and comparative example 2) and some distinguishing features of the present invention in preparation technology.
Can draw from the result of table 2, this patent disclose preparation method achieve by the amorphous crude product of rope fluorine cloth Wei from the solution of organic solvent to the direct transformation of stable crystal form, eliminate the step of converting between the crystal in original crystal formation 6 preparation method.Preparation method of the present invention is while acquisition rope fluorine cloth Wei single crystal form 6, achieve the purification of rope fluorine cloth Wei and refining, the high-purity raw medicine product of high purity more than 99.5% can be obtained from unbodied rope fluorine cloth Wei crude product one step, simultaneously, crystallization processes of the present invention is simply efficient, favorable repeatability, efficiently solves the deficiency of the existing preparation method of rope fluorine cloth Wei crystal formation 6.
The table 2 rope fluorine cloth Wei existing technology of preparing of crystal formation 6 and the inventive method synopsis
Claims (8)
1. a preparation method for rope fluorine cloth Wei crystal formation 6, is characterized in that, comprise the following steps:
(1) be dissolved in solvent by rope fluorine cloth Wei and obtain rope fluorine cloth Wei solution, wherein, described solvent is the mixture of cyclopentyl methyl ether or cyclopentyl methyl ether and other ether solvents;
(2) described rope fluorine cloth Wei solution is carried out crystallization;
(3) drying treatment is carried out after the solid filtering obtained by crystallization, drip washing.
2. preparation method according to claim 1, is characterized in that, in described solvent, the content of cyclopentyl methyl ether accounts for 60 ~ 100wt%.
3. preparation method according to claim 1, is characterized in that, other ether solvents described are any one or multiple mixture in isopropyl ether, dibutyl ether, methyl-phenoxide and dibenzyl ether.
4. preparation method according to claim 1, is characterized in that, in described rope fluorine cloth Wei solution, the volume mass ratio of solvent and rope fluorine cloth Wei is 5 mls/g ~ 50 mls/g.
5. preparation method according to claim 1, is characterized in that, described rope fluorine cloth Wei solution is by being heated to 70 DEG C ~ 95 DEG C until dissolve completely, and then carry out crystallization by cooling, recrystallization temperature is 0 ~ 25 DEG C.
6. preparation method according to claim 1, is characterized in that, in step (2), described rope fluorine cloth Wei solution is leaving standstill or crystallization under agitation condition, and stir speed (S.S.) is 0 ~ 100 rev/min.
7. preparation method according to claim 1, is characterized in that, the rate of temperature fall of described cooling is 0.5 ~ 10 DEG C/min.
8. preparation method according to claim 1, it is characterized in that, in step (3), when the solid obtained is filtered in drip washing, the mixture that the solvent used is isopropyl ether or isopropyl ether and any one or multiple organic solvent, wherein the content of isopropyl ether accounts for 80 ~ 100wt% (mass percent).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510234375.9A CN104829673B (en) | 2015-03-12 | 2015-05-08 | A kind of preparation method of rope fluorine cloth Wei crystal formation 6 |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2015101087435 | 2015-03-12 | ||
| CN201510108743 | 2015-03-12 | ||
| CN201510234375.9A CN104829673B (en) | 2015-03-12 | 2015-05-08 | A kind of preparation method of rope fluorine cloth Wei crystal formation 6 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104829673A true CN104829673A (en) | 2015-08-12 |
| CN104829673B CN104829673B (en) | 2017-10-27 |
Family
ID=53807907
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510234375.9A Expired - Fee Related CN104829673B (en) | 2015-03-12 | 2015-05-08 | A kind of preparation method of rope fluorine cloth Wei crystal formation 6 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104829673B (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN109369757A (en) * | 2018-11-12 | 2019-02-22 | 浙江外国语学院 | A method of preparing Suo Feibuwei crystal form 6 |
| CN111233956A (en) * | 2018-11-29 | 2020-06-05 | 西安百淞医药科技有限公司 | Crystal form of sofosbuvir and preparation method thereof |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102858790A (en) * | 2010-03-31 | 2013-01-02 | 吉利德制药有限责任公司 | Nucleoside Phosphoramidates |
| CN103052646A (en) * | 2010-07-19 | 2013-04-17 | 吉里德科学公司 | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
| US20130136776A1 (en) * | 2011-11-29 | 2013-05-30 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis c virus |
| US8618076B2 (en) * | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
| 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 |
-
2015
- 2015-05-08 CN CN201510234375.9A patent/CN104829673B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8618076B2 (en) * | 2009-05-20 | 2013-12-31 | Gilead Pharmasset Llc | Nucleoside phosphoramidates |
| CN102858790A (en) * | 2010-03-31 | 2013-01-02 | 吉利德制药有限责任公司 | Nucleoside Phosphoramidates |
| CN103052646A (en) * | 2010-07-19 | 2013-04-17 | 吉里德科学公司 | Methods for the preparation of diasteromerically pure phosphoramidate prodrugs |
| US20130136776A1 (en) * | 2011-11-29 | 2013-05-30 | Gilead Pharmasset Llc | Compositions and methods for treating hepatitis c virus |
| 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 |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN109369757A (en) * | 2018-11-12 | 2019-02-22 | 浙江外国语学院 | A method of preparing Suo Feibuwei crystal form 6 |
| CN109369757B (en) * | 2018-11-12 | 2020-12-29 | 浙江外国语学院 | Method for preparing Sofosbuvir crystal form 6 |
| CN111233956A (en) * | 2018-11-29 | 2020-06-05 | 西安百淞医药科技有限公司 | Crystal form of sofosbuvir and preparation method thereof |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104829673B (en) | 2017-10-27 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2020518662A (en) | Polymorphism of compound, production method and use thereof | |
| US10364244B2 (en) | Crystal form of pyrroloquinoline quinone sodium salt and preparation method and use thereof | |
| CN105801645B (en) | The method for preparing Suo Feibuwei crystal form 6 | |
| CN104829673A (en) | Preparation method of sofosbuvir crystal form 6 | |
| CN102659818B (en) | Hydrochloric acid cefotiam crystalline compound, preparation method thereof and medicine combination containing compound | |
| CN105753904B (en) | A kind of process for purification of Tedizolid Phosphate | |
| CN110563600B (en) | Preparation method of oseltamivir phosphate | |
| CN102924483A (en) | Ceftazidime crystal compound, preparation method of compound and pharmaceutical composition of compound in sterile mixed powder form | |
| CN105061420B (en) | A kind of crystal formation of JAK inhibitor and its preparation method and application | |
| US8148542B2 (en) | Method for producing crystal polymorphs of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5-thiazolecarboxylic acid | |
| CN102558182A (en) | Ertapenem sodium crystal form E and preparation method thereof | |
| CN102491918A (en) | Alanyl glutamine compound and preparation method thereof | |
| CN111517980A (en) | N- [8- (2-hydroxybenzoyl) amino ] caprylic acid monopotassium crystal type compound, preparation method and application | |
| CN107814802A (en) | A kind of new method for preparing citric acid tropsch imatinib medicinal crystal-form | |
| US9169257B2 (en) | Crystal forms of adefovir dipivoxil and processes for preparing the same | |
| CN106674321A (en) | Preparation method of sofosbuvir crystal form 6 | |
| CN109400539A (en) | A kind of methylpyrazine derivative semihydrate | |
| CN106632024A (en) | Preparation method of ibuprofen-nicotinamide eutectic through solvent | |
| CN104557881A (en) | Preparation method of pazopanib hydrochloride crystal form | |
| CN108727417B (en) | Polycyclic compound sodium salt, and polycrystalline type, preparation method and application thereof | |
| CN109516991A (en) | A kind of citric acid tropsch imatinib crystal-form compound and preparation method thereof | |
| CN101195618A (en) | Method for producing beta crystal system anhydrous aztreonam | |
| CN115650870B (en) | Method for preparing high-purity pentetic acid and application thereof | |
| CN107337708A (en) | Pidotimod novel crystal forms and preparation method thereof | |
| CN108084201B (en) | Oxoindolspirotetrahydrofuran skeleton material, crystal thereof and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20171027 Termination date: 20200508 |