CN106674321A - Preparation method of sofosbuvir crystal form 6 - Google Patents
Preparation method of sofosbuvir crystal form 6 Download PDFInfo
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- CN106674321A CN106674321A CN201611175337.1A CN201611175337A CN106674321A CN 106674321 A CN106674321 A CN 106674321A CN 201611175337 A CN201611175337 A CN 201611175337A CN 106674321 A CN106674321 A CN 106674321A
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- 239000013078 crystal Substances 0.000 title claims abstract description 205
- 238000002360 preparation method Methods 0.000 title claims abstract description 86
- TTZHDVOVKQGIBA-IQWMDFIBSA-N sofosbuvir Chemical compound N1([C@@H]2O[C@@H]([C@H]([C@]2(F)C)O)CO[P@@](=O)(N[C@@H](C)C(=O)OC(C)C)OC=2C=CC=CC=2)C=CC(=O)NC1=O TTZHDVOVKQGIBA-IQWMDFIBSA-N 0.000 title abstract description 12
- 229960002063 sofosbuvir Drugs 0.000 title abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 52
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 239000012535 impurity Substances 0.000 claims abstract description 26
- 150000001335 aliphatic alkanes Chemical class 0.000 claims abstract description 24
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 claims abstract description 18
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 186
- 238000005755 formation reaction Methods 0.000 claims description 186
- 239000012043 crude product Substances 0.000 claims description 79
- 239000000047 product Substances 0.000 claims description 51
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 48
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 44
- 150000001298 alcohols Chemical class 0.000 claims description 42
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 42
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 40
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 31
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 26
- 239000012046 mixed solvent Substances 0.000 claims description 25
- 238000001035 drying Methods 0.000 claims description 19
- 238000012805 post-processing Methods 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 16
- 238000013019 agitation Methods 0.000 claims description 14
- 239000004744 fabric Substances 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- NHTMVDHEPJAVLT-UHFFFAOYSA-N Isooctane Chemical compound CC(C)CC(C)(C)C NHTMVDHEPJAVLT-UHFFFAOYSA-N 0.000 claims description 9
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 238000000746 purification Methods 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 25
- 238000004128 high performance liquid chromatography Methods 0.000 abstract description 24
- 229940079593 drug Drugs 0.000 abstract description 15
- 238000000034 method Methods 0.000 abstract description 12
- 238000002425 crystallisation Methods 0.000 abstract description 8
- 230000008025 crystallization Effects 0.000 abstract description 8
- 239000007787 solid Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 6
- 238000007670 refining Methods 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 39
- 238000000634 powder X-ray diffraction Methods 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- 239000012065 filter cake Substances 0.000 description 11
- 239000000356 contaminant Substances 0.000 description 10
- 238000001514 detection method Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- 208000005176 Hepatitis C Diseases 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 3
- 230000007547 defect Effects 0.000 description 3
- 238000001144 powder X-ray diffraction data Methods 0.000 description 3
- 229940076563 sovaldi Drugs 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000711549 Hepacivirus C Species 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000003111 delayed effect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- -1 tert-butyl alcohols Chemical class 0.000 description 2
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical class CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- DBUJFULDVAZULB-UHFFFAOYSA-N 1-methoxypentane Chemical compound CCCCCOC DBUJFULDVAZULB-UHFFFAOYSA-N 0.000 description 1
- 0 CC(C)OC([C@](C)*(C)[C@@](C)*(OC[C@]1O[C@@](*(C=CC(*2)=O)C2=O)C(C)(C)[C@@]1OC)Oc1ccccc1)=O Chemical compound CC(C)OC([C@](C)*(C)[C@@](C)*(OC[C@]1O[C@@](*(C=CC(*2)=O)C2=O)C(C)(C)[C@@]1OC)Oc1ccccc1)=O 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 208000006154 Chronic hepatitis C Diseases 0.000 description 1
- 229910016523 CuKa Inorganic materials 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- 208000022120 Jeavons syndrome Diseases 0.000 description 1
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 1
- 241000218636 Thuja Species 0.000 description 1
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 208000020403 chronic hepatitis C virus infection Diseases 0.000 description 1
- JVSWJIKNEAIKJW-UHFFFAOYSA-N dimethyl-hexane Natural products CCCCCC(C)C JVSWJIKNEAIKJW-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229910002804 graphite Inorganic materials 0.000 description 1
- 239000010439 graphite Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 208000010710 hepatitis C virus infection Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000010413 mother solution Substances 0.000 description 1
- 238000011017 operating method Methods 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of a sofosbuvir crystal form 6. The preparation method comprises the following steps: mixing a solution formed by a sofosbuvir coarse product and a water-containing alcohol solvent with alkane, and performing crystallization to obtain the sofosbuvir crystal form 6. According to the sofosbuvir coarse product, the mass content of a special impurity II is not greater than 3%, the mass content is percentage of mass of the specific impurity II in the sofosbuvir coarse product, and the specific impurity II is pentafluorophenol. The preparation method provided by the invention is simple and efficient in crystallization process, short in step, high in yield, good in repeatability and obvious in refining effect of the specific impurity II; and the obtained product is good in stability and high in purity, meets the demands of an oral solid preparation, meets the demands (HPLC purity is greater than 99.50% and the maximum single impurity is smaller than 0.1%) of raw material medicines, is green and environmental-friendly, and is suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of Suo Feibuwei crystal formations 6.
Background technology
Suo Feibuwei (trade names：Sovaldi, common name：Sofosbuvir, before entitled GS-7977, PSI-7977),
Chemical name：(S) -2- { [(2R, 3R, 4R, 5R) -5- (2,4- dioxo -3,4- dihydro -2H- pyrimidine -1- bases) the fluoro- 3- hydroxyls of -4-
Base -4- methyl-tetrahydro furan -2- ylmethoxies]-phosphonamino }-isopropyl propionate.CAS Registry Number is：1190307-88-
0, chemical structural formula is as follows：
Suo Feibuwei is a kind of hepatitis C viruss (HCV) core of U.S.'s Ji Leadd B.V (Glead Sciences) research and development
Thuja acid analog NS5B AG14361, it is adaptable to as composition or independent role in combination antiviral therapy scheme
In the consistent specific protein needed for blocking hepatitis c viral replication so as to treat chronic hepatitis C infection, it is mainly used in base
Because of the treatment of 1 type, 2 types, 3 types and 4 type chronic hepatitis Cs (Hepatitis C) adult patient.Suo Feibuwei (trade names：
Sovaldi, 400mg tablet) ratify in the U.S. in the acquisition of on December 6th, 2013 food and medicine Surveillance Authority of the U.S. (FDA)
City, the Nikkei of January 16 in 2014 Europe drug administration (EMEA) approval is in EU countries's listing.Sovaldi be it is first it is granted can
For the medicine of the full oral treatment regimes of hepatitis C, when treating for specific gene type (2 types, 3 types) chronic hepatitis C,
The demand to conventional injection interfering effects of drug element (IFN) can be eliminated.The medicine is not yet listed at home, good market prospects.
Crystal formation medicine (polymorphic drugs) refers to active ingredient with the solid drugs of specific crystal formation state presence,
Polymorph in pharmaceuticals refers to that medicine has two or more different crystal forms state of matter.Polymorph in pharmaceuticals is in solid drugs
The natural phenomena of generally existing.Because the medicine of different crystal forms may affect its dissolution in vivo, absorb, and then may be
Clinical efficacy and the safety of medicine are affected to a certain extent.Therefore, for polymorph medicine, in developing solid oral formulations
When, be conducive to selection a kind of meaningful on clinical treatment to crystal formation research and stablize controllable active component.For Suo Feibu
Wei, has reported at present it and there is polymorphism, and original grinds the advantage that crystal formation 6 is principle active component in listing finished medicines
Crystal formation.
Lucky Leadd B.V's original is ground patent CN102858790A and discloses 6 kinds of crystal formations of Suo Feibuwei and preparation method thereof, beautiful
State's patent US8648076 emphasis Suo Feibuwei crystal formations 6 are described and preparation method protection.
Patent CN102858790A describes 6 kinds of crystal formation features of Suo Feibuwei, and discloses corresponding XPRD signs spectrum
Figure and characterize data, and explicitly point out crystal formation 1 and be by crystal formation 2, crystal formation 3, crystal formation 4, crystal formation 5 or unformed be transformed.And
Crystal formation 2, crystal formation 3, crystal formation 4, crystal formation 5 are to be crystallized respectively to obtain from different solvents by unformed Suo Feibuwei.The system of crystal formation 6
Need less to the utmost to turn crystalline substance through two steps, i.e., crystal formation 2,3,4,5 or unformed is converted into crystal formation 1, and crystal formation 1 is then converted to crystal formation 6.
Patent US8648076 reports the preparation method of 2 kinds of crystal formations 6, is obtained from 1 turn of crystalline substance of crystal formation：
Method 1：Because crystal formation 1 easily absorbs water deliquescence, by under the powder of crystal formation 1 humidity disposed within, it is transformed into after a few days solidifying
Glue, by the spawn grind into powder, and this powder is placed in place 6~10 weeks in open-top receptacle after sample just slowly
It is transformed into crystal formation 6.
Method 2：To add under the room temperature of crystal formation 1 in 5mg/mL~50mg/mL water, the stirring at room temperature or 50 DEG C turns brilliant number 40
Crystal formation 6 is obtained more than hour.
And patent CN102858790A and US8648076 are specialized, crystal formation 6 cannot be obtained from organic solvent.
Nanjing Qi Chang Pharmaceutical Technology Co., Ltd in 2015 discloses Suo Feibuwei and passes through by patent CN104829673A
Ether solvent crystallize goes out the preparation method of crystal formation 6.Using cyclopentyl-methyl ether as main crystallization solvent in the patent, coordinate
Using ether solvents such as methyl tertiary butyl ether(MTBE), diisopropyl ether or butyl oxides.But, we are respectively to embodiment 6 and 7 through three times
Repeat to test, the Suo Feibuwei for no matter adopting is amorphous products or crystal formation 1, can not separate out crystal, only one oily
Thing is separated out from organic solvent, and viscous wall is serious.
In addition, reported according to document [J.Med.Chem.2010,53 (17), 7202-7218], Suo Feibuwei crude drug
In syntheti c route, quality important of the Pentafluorophenol (II) as process contaminants to product API, therefore, it is necessary to pass through
Crystallization processes are strict controlled in appropriate scope, to meet the standard of crude drug.
Using the method for column chromatography, the impurity is dispelled in document, but the method for column chromatography has Financial cost height, is not suitable for
The defects such as industrialized production.
And the crystal formation preparation method that patent CN102858790A and US8648076 are reported does not have refining effect, it is necessary to
Purification is qualified before Suo Feibuwei medicinal crystal-forms are prepared.
In sum, widely using with Suo Feibuwei medicines, and the pain of hepatitis C patient is released as early as possible, it would be highly desirable to solve
A difficult problem prepared by the Suo Feibuwei crystal formations existing for patent CN102858790A and US8648076, i.e., must be converted into by crystal formation 1
Crystal formation 6, and crystal formation 1 needs to be obtained by 2,3,4,5 or unformed turns of crystalline substances of crystal formation, complex steps, not with refining effect, raw material
Medicine purity requirement is high, and high cost is not suitable for the defects such as industrialized production.
The content of the invention
The technical problem to be solved be in order to overcome prior art in Suo Feibuwei crystal formations 6 preparation need by
2,3,4,5 or unformed turns of crystalline substances of crystal formation are crystal formation 1, then are converted into crystal formation 6, complex steps, high cost by crystal formation 1, and are not had
Refining effect, it is not easy to reach crude drug standard, is not suitable for the defects such as industrialized production；And it is brilliant to provide a kind of Suo Feibuwei
The preparation method of type 6.The preparation method crystallization processes of the present invention are simply efficient, and step is few, high income, reproducible, to specific
The purification effect of impurity is good, and obtained product purity is high, can reach the requirement of crude drug, and environmental protection is suitable for industrialization
Production.
The present invention proposes a kind of preparation method of Suo Feibuwei crystal formations 6, and it is comprised the following steps：By Suo Feibuwei crude products
The solution formed with aqueous alcohols solvent, then mix with alkane, crystallize, obtain Suo Feibuwei crystal formations 6；Described Suo Fei
Cloth Wei crude product is not more than 3% Suo Feibuwei crude products for the mass content of specific impurities II, and described mass content refers to specific
The quality of impurity II accounts for the percentage ratio of Suo Feibuwei crude product qualities；Described specific impurities II are Pentafluorophenol.
In the preparation method of described Suo Feibuwei crystal formations 6, in described " alcohols solvent containing water ", described water with
The volume ratio of described alcohols solvent preferably 0.02~0.05, such as 0.02,0.03,0.04 or 0.05, described volume ratio
Value refers to the ratio of the volume of water and the volume of alcohols solvent.
In the preparation method of described Suo Feibuwei crystal formations 6, in described " alcohols solvent containing water ", described " alcohol
One or more in class solvent " preferably methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol and isobutanol；Further
One or more in preferred alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol and isobutanol.
In the preparation method of described Suo Feibuwei crystal formations 6, described " aqueous alcohols solvent " and described Suo Feibu
Preferred 0.5mL/g~the 10.0mL/g of volume mass ratio, the further preferred 2.0mL/g~9.0mL/g of Wei crude product, for example
3.1mL/g, 3.2mL/L, 4.1mL/g, 4.2mL/g or 6.3mL/g.
In the preparation method of described Suo Feibuwei crystal formations 6, described " Suo Feibuwei crude products and aqueous alcohols solvent shape
Into solution " preferably 5 DEG C~65 DEG C, further preferred 5 DEG C~50 DEG C of temperature；Such as 5 DEG C~10 DEG C, 10 DEG C~15 DEG C, 20
DEG C~25 DEG C, 40 DEG C~45 DEG C or 45 DEG C~50 DEG C.
In the preparation method of described Suo Feibuwei crystal formations 6, the preferred normal heptane of described alkane, normal hexane, 2- hexanes, just
One or more in octane and isobutyltrimethylmethane..
In the preparation method of described Suo Feibuwei crystal formations 6, the volume mass ratio of described alkane and Suo Feibuwei crude products
Be worth preferred 3.0mL/g~50.0mL/g, further preferred 5.0mL/g~45.0mL/g, such as 6.0mL/g, 12.0mL/L,
13.0mL/g, 15.0mL/g, 20.0mL/g, 22.0mL/g, 30.0mL/g or 40.0mL/g.
In the preparation method of described Suo Feibuwei crystal formations 6, described Suo Feibuwei crude product Ke Yi Wei Suo Feibuwei crystal formations 1
Crude product, the crude product of Suo Feibuwei crystal formations 2, the crude product of Suo Feibuwei crystal formations 3, the crude product of Suo Feibuwei crystal formations 4, the crude product of Suo Feibuwei crystal formations 5
With one or more in the unformed crude products of Suo Feibuwei.Described Suo Feibuwei crude products for specific impurities II mass content not
Suo Feibuwei crude products more than 3%；Described specific impurities II are Pentafluorophenol.
In the preparation method of described Suo Feibuwei crystal formations 6, the preferred Deca of mode of described mixing；Described Deca
Preferred 1mL/min~the 100mL/min of speed, such as further preferred 1mL/min~80mL/min, 1.4mL/min, 2.8mL/
Min, 12.6mL/min, 13.6mL/min, 51.7mL/min, 52.0mL/min, 52.5mL/min or 68.7mL/min.
In the preparation method of described Suo Feibuwei crystal formations 6, described crystallize is preferably carried out under agitation, described
Preferably 60 revs/min~500 revs/min of mixing speed, further preferred 200 revs/min~260 revs/min, such as 200 turns/
Minute, 210 revs/min, 230 revs/min, 250 revs/min or 260 revs/min.
In the preparation method of described Suo Feibuwei crystal formations 6, preferably 0~50 DEG C of the temperature of described crystallize is further excellent
Select 10 DEG C~35 DEG C.
In the preparation method of described Suo Feibuwei crystal formations 6, preferably 10 hours~96 hours time of described crystallize, enter
One step preferably 12 hours~48 hours, such as 15 hours, 16 hours, 24 hours, 34 hours, 36 hours or 44 hours.
In the preparation method of described Suo Feibuwei crystal formations 6, described " Suo Feibuwei crude products and aqueous alcohols solvent shape
Into solution " preferably obtained using following steps：By Suo Feibuwei dissolving crude products in aqueous alcohols solvent, Suo Feibu is obtained
The solution that Wei crude product is formed with aqueous alcohols solvent.Preferably 5 DEG C~65 DEG C of the temperature of described dissolving, further preferably
5 DEG C~50 DEG C；Such as 5 DEG C~10 DEG C, 10 DEG C~15 DEG C, 20 DEG C~25 DEG C, 40 DEG C~45 DEG C or 45 DEG C~50 DEG C.
The preparation method of described Suo Feibuwei crystal formations 6, preferably includes following post-processing step：By Suo Feibuwei crystal formations 6
Filter, wash, being dried to obtain Suo Feibuwei crystal formations 6 after purification.
Described filters the conventional method that can adopt the generic operation in this area, using filter paper or filter-cloth filtering.It is described
The preferred Medium speed filter paper of filter paper；Described filter cloth preferably 200 mesh~300 mesh filter clothes.Described washing can be using in this area
The conventional method of the generic operation, washs the mixed solvent or water of the preferred alcohols solvent of the solvent and alkane for adopting.Described alcohols
One or more in the preferred methanol of solvent, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol and isobutanol；It is further excellent
Select one or more in ethanol, isopropanol, n-butyl alcohol, isobutanol and the tert-butyl alcohol.The preferred normal heptane of described alkane, just oneself
One or more in alkane, normal octane and isobutyltrimethylmethane..Described the mixed solvent of alkane " alcohols solvent with " preferably isopropanol with
The mixed solvent of the mixed solvent of normal heptane, the mixed solvent of ethanol and normal hexane, ethanol and normal heptane, n-butyl alcohol and normal octane
Mixed solvent, isobutanol and isobutyltrimethylmethane. mixed solvent, isopropanol and 2- hexane mixed solvents, isobutanol and normal hexane mixed solvent
Or the tert-butyl alcohol and normal heptane mixed solvent.
The volume ratio of the alcohols solvent described in described the mixed solvent of alkane " alcohols solvent with " and described alkane
It is preferred that 5:1~1:5, further preferred 3:1~1:3, such as 2:3、1:3 or 3:4.The number of times of described washing preferably 1 time~3
It is secondary.Described drying can adopt the conventional method of the generic operation in this area, described drying to be preferably vacuum dried；Described
Vacuum drying is carried out preferably in vacuum drying oven.Preferably 30 DEG C~70 DEG C, further preferred 45 DEG C of the temperature of described drying
~60 DEG C, such as 45 DEG C~50 DEG C.Preferably 10 hours~50 hours time of described drying；Further preferred 16 hours~30
Hour, such as 16 hours, 18 hours, 20 hours or 28 hours；Described vacuum drying pressure preferably -0.008MPa~-
0.1MPa。
Obtained Suo Feibuwei crystal formations 6 of the invention, yield is more than 90.0%；HPLC purity is more than 99.50%, and maximum is single
Impurity is less than 0.10%, reaches crude drug standard.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can combination in any, obtain final product the present invention each preferably
Example.
Agents useful for same of the present invention and raw material are commercially available.
In the present invention, described room temperature refers to that ambient temperature is 10 DEG C~35 DEG C.
The present invention positive effect be：The preparation method crystallization processes of the present invention are simply efficient, and step is short, yield
Height, reproducible, obvious to the refining effect of specific impurities II, products obtained therefrom good stability, purity is high, meets and is used as orally admittedly
The requirement of body preparation, meet crude drug requirement (HPLC purity is more than 99.50%, it is maximum single it is miscellaneous is less than 0.1%), green ring
Protect, be suitable for industrialized production.
Description of the drawings
Fig. 1 is the XRD spectra of the Suo Feibuwei obtained according to embodiments of the invention 1.
Fig. 2 is the XPRD spectrograms of the Suo Feibuwei obtained according to embodiments of the invention 1.
Fig. 3 is the DSC spectrograms of the Suo Feibuwei obtained according to embodiments of the invention 1.
Fig. 4 is the TGA spectrograms of the Suo Feibuwei obtained according to embodiments of the invention 1.
Fig. 5 is the XPRD spectrograms of the Suo Feibuwei obtained according to embodiments of the invention 2.
Fig. 6 is the XPRD spectrograms of the Suo Feibuwei obtained according to embodiments of the invention 3.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality
Among applying a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product description is selected.
In the preparation technology of the Suo Feibuwei crystal formations 6 of the present invention, the Suo Feibuwei crude products that used (including Suo Feibuwei without
Sizing, crystal formation 1, crystal formation 2, crystal formation 3, crystal formation 4 and crystal formation 5 etc.) report (such as according to existing document：J.Med.Chem.2010,
53 (17), 7202-7218) method prepare Suo Feibuwei products, other solvents and reagent are pure using commercially available chemistry or analyze
It is pure.
Embodiment 1
10 DEG C~15 DEG C, in single-necked flask by the crude product of Suo Feibuwei crystal formations 1 (5.0g, HPLC purity 97.3%, it is specific miscellaneous
Matter II mass content is 2.4%；Described mass content refers to that the quality of specific impurities II accounts for the hundred of Suo Feibuwei crude product qualities
Divide ratio；Described specific impurities II are dissolved completely in isopropanol (20mL) for Pentafluorophenol, add water (0.6mL, water：Isopropyl
The solution that alcohol volume ratio is formed for 0.03) get Suo Feibuwei crude products with aqueous isopropanol, then by the Suo Feibuwei crude products
The solution formed with aqueous isopropanol is proceeded in constant pressure funnel, standby.
Normal heptane (30mL) is added to being furnished with churned mechanically there-necked flask, mechanical agitation is opened, speed of agitator is 260
Rev/min, under room temperature (10 DEG C~35 DEG C), the solution that Suo Feibuwei crude products and aqueous isopropanol are formed is passed through into constant pressure addition
Funnel is slowly dropped in n-heptane solution, takes about 15 minutes, and drop finishes can obtain milky suspension.Continue room temperature (10 DEG C~35
DEG C) 15 hours crystallizes of stirring, filtered with Medium speed filter paper, the mixed solvent 10mL (isopropanols of filter cake isopropanol and normal heptane：Just
Heptane volume ratio is 2：3) once, 45 DEG C~50 DEG C are vacuum dried 16 hours (vacuum -0.008MPa), get Suo Feibuwei for drip washing
Product 4.74g, yield 94.8%, HPLC purity 99.74%, maximum single contaminant (impurity II) 0.04%.
Mother solution stands storage 5 days, can separate out Suo Feibuwei monocrystalline, and monocrystalline figure (XRD) is as shown in figure 1, the crystal is divided
Diffracted intensity data, CuKa radiation, graphite monochromator, single conduit are collected from rear employing Bruker SMART APEX-II diffractometers
Diameter Ψ=0.50mm, crystal is with ccd detector apart from d=60.3mm, pipe pressure 40KV, pipe flow 30mA, scan mode：ψ/ω sweeps
Retouch, it is 9575 to collect total diffraction points, and independent diffraction points are 4822, and observable points are 4778, its measurement result
For：Crystal is in water white transparency column, and diffraction experiment crystal size is 0.15 × 0.18 × 0.26mm, belongs to monoclinic system, space
Group P21, cell parameter：A=12.956 (3), b=6.2049 (12),α=γ=90.0 °, β=93.87
°, (3) unit cell volumeAsymmetry unit number Z=2 in structure cell.
The crystal product that drying is obtained is carried out into powder X-ray diffraction (XPRD) detection, its spectrogram is as shown in Figure 2.With Fig. 2
The powder X-ray diffraction data of corresponding Suo Feibuwei crystal formations 6 are as shown in table 1.The DSC of the Suo Feibuwei that embodiment 1 is obtained
As shown in figure 3, the endothermic transition of Suo Feibuwei crystal formations 6 is at 126.0 DEG C ± 2 DEG C, fusing absorbs thermal spike 100.7J/g to spectrogram.Implement
The TGA spectrograms of the Suo Feibuwei that example 1 is obtained are as shown in figure 4, TGA weightlessness 0.36%.
The XPRD characteristic peak positions of the gained Suo Feibuwei products of 1 embodiment of table 1
The original that the result shown in XPRD spectrograms is reported with patent CN102858790A and US8648076 grinds the characteristic spectrum of crystal formation 6
Figure is consistent, it can be verified that the crystal is Suo Feibuwei crystal formations 6.
Embodiment 2
5 DEG C~10 DEG C, in single-necked flask by the crude product of Suo Feibuwei crystal formations 1 (1.0kg, HPLC purity 98.3%, it is specific miscellaneous
Matter II mass content 2.1%) be dissolved completely in ethanol (3L), be subsequently adding water (100mL) get Suo Feibuwei crude products with it is aqueous
The solution that formed of ethanol, then the solution that Suo Feibuwei crude products are formed with aqueous ethanol is proceeded in constant pressure funnel,
It is standby.
Normal hexane (20L) is added to being furnished with churned mechanically reactor, mechanical agitation is opened, rotating speed is 230 revs/min
Clock, under room temperature (10 DEG C~35 DEG C), the solution that Suo Feibuwei crude products are formed with aqueous ethanol is delayed by constant pressure funnel
It is slow to instill in hexane solution, about 60 minutes are taken, drop finishes can obtain milky suspension.Continue (10 DEG C~35 DEG C) stirrings of room temperature
44 hours crystallizes, with 200 mesh~300 mesh filter-cloth filterings, filter cake ethanol and normal hexane mixed solvent 1L (ethanol：Normal hexane body
Product is than being 1:3) once, 45 DEG C~50 DEG C are vacuum dried 20 hours (vacuum -0.008MPa), get Suo Feibuwei products for drip washing
936g, yield 93.6%, HPLC purity 99.77%, maximum single contaminant (impurity II) 0.03%.
The crystal product that drying is obtained is carried out into powder X-ray diffraction (PXRD) detection, its spectrogram is as shown in figure 5, and Fig. 5
The powder X-ray diffraction data of corresponding Suo Feibuwei crystal formations 6 are as shown in table 2.Jing is analyzed, the test result and patent of product
The characteristic spectrum that the Suo Feibuwei originals of report grind crystal formation 6 is consistent, it was demonstrated that the product is Suo Feibuwei crystal formations 6.
The XPRD characteristic peak positions tables of the gained Suo Feibuwei products of 2 embodiment of table 2
The original that the result shown in XPRD spectrograms is reported with patent CN102858790A and US8648076 grinds the characteristic spectrum of crystal formation 6
Figure is consistent, it can be verified that the crystal is Suo Feibuwei crystal formations 6.
Embodiment 3
At 40 DEG C~45 DEG C, in single-necked flask by the crude product of Suo Feibuwei crystal formations 3 (100g, HPLC purity 97.1%, it is specific
Impurity II mass contents 2.8%) be dissolved completely in n-butyl alcohol (600mL), add water (30mL) get Suo Feibuwei crude products with
The solution that aqueous n-butyl alcohol is formed, then proceeds to constant pressure addition by the solution that Suo Feibuwei crude products are formed with aqueous n-butyl alcohol
It is standby in funnel.
Normal octane (3L) is added to being furnished with churned mechanically reactor, mechanical agitation is opened, rotating speed is 200 turns/min,
Under room temperature (10 DEG C~35 DEG C), the solution that Suo Feibuwei crude products and aqueous n-butyl alcohol are formed is slow by constant pressure funnel
In instilling normal octane solution, about 50 minutes are taken, drop finishes can obtain milky suspension.Continue (10 DEG C~35 DEG C) stirrings 36 of room temperature
Hour crystallize, with 200 mesh~300 mesh filter-cloth filterings, filter cake n-butyl alcohol and normal octane mixed solvent 300mL (n-butyl alcohol：It is just pungent
Alkane volume ratio is 3:4) once, 45 DEG C~50 DEG C are vacuum dried 28 hours, and vacuum -0.008MPa, get Suo Feibuwei is produced for drip washing
Product 96.2g, yield：96.2%, HPLC purity 99.87%, maximum single contaminant 0.03%.
The crystal product that drying is obtained is carried out into powder X-ray diffraction (XPRD) detection, its spectrogram is as shown in fig. 6, and Fig. 6
The powder X-ray diffraction data of corresponding Suo Feibuwei crystal formations 6 are as shown in table 3.Jing is analyzed, the test result and patent of product
The characteristic spectrum that the Suo Feibuwei originals of report grind crystal formation 6 is consistent, it was demonstrated that the product is Suo Feibuwei crystal formations 6.
The XPRD characteristic peak positions of the gained Suo Feibuwei products of 3 embodiment of table 3
The original that the result shown in XPRD spectrograms is reported with patent CN102858790A and US8648076 grinds the characteristic spectrum of crystal formation 6
Figure is consistent, it can be verified that the crystal is Suo Feibuwei crystal formations 6.
Embodiment 4
At 45 DEG C~50 DEG C, in single-necked flask by the crude product of Suo Feibuwei crystal formations 4 (100g, HPLC purity 97.1%, it is specific
Impurity II mass contents 2.8%) be dissolved completely in the tert-butyl alcohol (400mL), add water (8mL) get Suo Feibuwei crude products with it is aqueous
The solution that formed of the tert-butyl alcohol, then the solution that the Suo Feibuwei crude products are formed with the aqueous tert-butyl alcohol is proceeded to into constant pressure addition leakage
It is standby in bucket.
Normal heptane (1.3L) is added to being furnished with churned mechanically reactor, mechanical agitation is opened, rotating speed is 200 revs/min
Clock, under room temperature (10 DEG C~35 DEG C), by the solution that Suo Feibuwei crude products and the aqueous tert-butyl alcohol are formed constant pressure funnel is passed through
In being slowly dropped into n-heptane solution, about 30 minutes are taken, drop finishes can obtain milky suspension.Continue room temperature (10 DEG C~35 DEG C) to stir
15 hours crystallizes are mixed, with 200 mesh~300 mesh filter-cloth filterings, once, 45 DEG C~50 DEG C vacuum are done for filter cake water (100mL) drip washing
Dry 18 hours (vacuum -0.008MPa), get Suo Feibuwei product 95.7g, yield 95.7%, HPLC purity 99.73% is maximum
Single contaminant 0.04%.
The crystal product that drying is obtained is carried out into powder X-ray diffraction (XPRD) detection, Jing analyses, the test result of product
It is consistent with the characteristic spectrum that the Suo Feibuwei originals of patent report grind crystal formation 6 that (patent CN102858790A and US8648076 are reported
Original grinds crystal formation 6), it was demonstrated that the product is Suo Feibuwei crystal formations 6.
Embodiment 5
At 20 DEG C~25 DEG C, in single-necked flask by the crude product of Suo Feibuwei crystal formations 5 (10g, HPLC purity 97.1%, it is specific
Impurity II mass contents 2.8%) be dissolved completely in isobutanol (40mL), add water (2mL) get Suo Feibuwei crude products with it is aqueous
The solution that formed of isobutanol, then the solution that the Suo Feibuwei crude products are formed with aqueous isobutanol is proceeded to into constant pressure addition leakage
It is standby in bucket.
Isobutyltrimethylmethane. (400mL) is added to being furnished with churned mechanically reactor, mechanical agitation is opened, rotating speed is 210 revs/min
Clock, under room temperature (10 DEG C~35 DEG C), by the solution that Suo Feibuwei crude products and aqueous isobutanol are formed constant pressure funnel is passed through
In being slowly dropped into isooctane solution, about 15 minutes are taken, drop finishes can obtain milky suspension.Continue room temperature (10 DEG C~35 DEG C) to stir
16 hours crystallizes are mixed, with 200 mesh~300 mesh filter-cloth filterings, filter cake isobutanol and isobutyltrimethylmethane. mixed solvent 10mL (isobutanol：
Isobutyltrimethylmethane. volume ratio is 3:4) once, 45 DEG C~50 DEG C are vacuum dried 28 hours (vacuum -0.008MPa), get Suo Feibu for drip washing
Wei product 9.2g, yield 92%, HPLC purity 99.73%, maximum single contaminant 0.06%.
The crystal product that drying is obtained is carried out into powder X-ray diffraction (XPRD) detection, Jing analyses, the test result of product
It is consistent with the characteristic spectrum that the Suo Feibuwei originals of patent report grind crystal formation 6 that (patent CN102858790A and US8648076 are reported
Original grinds crystal formation 6), it was demonstrated that the product is Suo Feibuwei crystal formations 6.
Embodiment 6
5 DEG C~10 DEG C, in single-necked flask by the amorphous crude products of Suo Feibuwei (1.0kg, HPLC purity 97.1%, it is specific
Impurity II mass contents 2.8%) be dissolved completely in isopropanol (3L), add water (150mL) get Suo Feibuwei crude products with it is aqueous
The solution that formed of isopropanol, then the solution that the Suo Feibuwei crude products are formed with aqueous isopropanol is proceeded to into constant pressure addition leakage
It is standby in bucket.
2- hexanes (15L) are added to being furnished with churned mechanically reactor, mechanical agitation is opened, rotating speed is 230 revs/min
Clock, under room temperature (10 DEG C~35 DEG C), by the solution that Suo Feibuwei crude products and aqueous isopropanol are formed constant pressure funnel is passed through
In being slowly dropped into aqueous solution, about 60 minutes are taken, drop finishes can obtain milky suspension.Continue (10 DEG C~35 DEG C) stirrings 24 of room temperature
Hour crystallize, with 200 mesh~300 mesh filter-cloth filterings, filter cake isopropanol and 2- hexane mixed solvent 500mL (isopropanols：2- oneself
Alkane mixed solvent volume ratio is 3:4) once, 45 DEG C~50 DEG C vacuum drying, 20 hours (vacuum -0.008MPa) obtains rope for drip washing
Fei Buwei product 935g, yield 93.5%, HPLC purity 99.65%, maximum single contaminant 0.05%.
The crystal product that drying is obtained is carried out into powder X-ray diffraction (XPRD) detection, Jing analyses, the test result of product
It is consistent with the characteristic spectrum that the Suo Feibuwei originals of patent report grind crystal formation 6 that (patent CN102858790A and US8648076 are reported
Original grinds crystal formation 6), it was demonstrated that the product is Suo Feibuwei crystal formations 6.
Embodiment 7
5 DEG C~10 DEG C, in single-necked flask by the crude product of Suo Feibuwei crystal formations 2 (1.0kg, HPLC purity 97.1%, it is specific miscellaneous
Matter II mass content 2.8%) it is dissolved completely in ethanol (3L), add water (90mL) get Suo Feibuwei crude products and aqueous ethanol
The solution of formation, then proceeds to the solution that the Suo Feibuwei crude products are formed with aqueous ethanol in constant pressure funnel, standby.
Normal heptane (20L) is added to being furnished with churned mechanically reactor, mechanical agitation is opened, rotating speed is 230 revs/min
Clock, under room temperature (10 DEG C~35 DEG C), the solution that Suo Feibuwei crude products are formed with aqueous ethanol is delayed by constant pressure funnel
It is slow to instill in n-heptane solution, about 60 minutes are taken, drop finishes can obtain milky suspension.Continue (10 DEG C~35 DEG C) stirrings of room temperature
24 hours crystallizes, with 200 mesh~300 mesh filter-cloth filterings, filter cake ethanol and normal heptane mixed solvent 3L (ethanol：Normal heptane body
Product is than being 1:3) once, 45 DEG C~50 DEG C are vacuum dried 20 hours (vacuum -0.008MPa), get Suo Feibuwei products for drip washing
956g, yield 95.6%, HPLC purity 99.75%, maximum single contaminant 0.06%.
The crystal product that drying is obtained is carried out into powder X-ray diffraction (XPRD) detection, Jing analyses, the test result of product
It is consistent with the characteristic spectrum that the Suo Feibuwei originals of patent report grind crystal formation 6 that (patent CN102858790A and US8648076 are reported
Original grinds crystal formation 6), it was demonstrated that the product is Suo Feibuwei crystal formations 6.
Embodiment 8
5 DEG C~10 DEG C, in single-necked flask by the crude product of Suo Feibuwei crystal formations 3 (1.0kg, HPLC purity 97.1%, it is specific miscellaneous
Matter II mass content 2.8%) be dissolved completely in isobutanol (3L), add water (120mL) get Suo Feibuwei crude products with it is aqueous
The solution that isobutanol is formed, then proceeds to constant pressure funnel by the solution that the Suo Feibuwei crude products are formed with aqueous isobutanol
In, it is standby.
Normal hexane (22L) is added to being furnished with churned mechanically reactor, mechanical agitation is opened, rotating speed is 230 revs/min
Clock, under room temperature (10 DEG C~35 DEG C), by the solution that Suo Feibuwei crude products and aqueous isobutanol are formed constant pressure funnel is passed through
In being slowly dropped into hexane solution, about 60 minutes are taken, drop finishes can obtain milky suspension.Continue room temperature (10 DEG C~35 DEG C) to stir
34 hours crystallizes are mixed, with 200 mesh~300 mesh filter-cloth filterings, filter cake isobutanol and normal hexane mixed solvent 1L (isobutanol：Just
Hexane volume ratio is 2:3) once, 45 DEG C~50 DEG C are vacuum dried 20 hours (vacuum -0.008MPa), get Suo Feibuwei for drip washing
Product 913g, yield 91.3%, HPLC purity 99.57%, maximum single contaminant 0.09%.
The crystal product that drying is obtained is carried out into powder X-ray diffraction (PXRD) detection, Jing analyses, the test result of product
It is consistent with the characteristic spectrum that the Suo Feibuwei originals of patent report grind crystal formation 6 that (patent CN102858790A and US8648076 are reported
Original grinds crystal formation 6), it was demonstrated that the product is Suo Feibuwei crystal formations 6.
Embodiment 9
5 DEG C~10 DEG C, in single-necked flask by the unformed crude products of Suo Feibuwei (1.0kg, HPLC purity 97.1%, it is specific
Impurity II mass contents 2.8%) be dissolved completely in the tert-butyl alcohol (4L), add water (120mL) get Suo Feibuwei crude products with it is aqueous
The solution that formed of the tert-butyl alcohol, then the solution that the Suo Feibuwei crude products are formed with the aqueous tert-butyl alcohol is proceeded to into constant pressure addition leakage
It is standby in bucket.
Normal heptane (12L) is added to being furnished with churned mechanically reactor, mechanical agitation is opened, rotating speed is 250 revs/min
Clock, under room temperature (10 DEG C~35 DEG C), by the solution that Suo Feibuwei crude products and the aqueous tert-butyl alcohol are formed constant pressure funnel is passed through
In being slowly dropped into n-heptane solution, about 60 minutes are taken, drop finishes can obtain milky suspension.Continue room temperature (10 DEG C~35 DEG C) to stir
24 hours crystallizes are mixed, with 200 mesh~300 mesh filter-cloth filterings, the filter cake tert-butyl alcohol and the normal heptane mixed solvent 1L (tert-butyl alcohols：Just
Heptane volume ratio is 2：3) once, 45 DEG C~50 DEG C are vacuum dried 20 hours (vacuum -0.008MPa), get Suo Feibuwei for drip washing
Product 917g, yield 91.7%, HPLC purity 99.63%, maximum single contaminant 0.08%.
The crystal product that drying is obtained is carried out into powder X-ray diffraction (PXRD) detection, Jing analyses, the test result of product
It is consistent with the characteristic spectrum that the Suo Feibuwei originals of patent report grind crystal formation 6 that (patent CN102858790A and US8648076 are reported
Original grinds crystal formation 6), it was demonstrated that the product is Suo Feibuwei crystal formations 6.
Comparative example 1 (with reference to the operation of 102858790,0459 section of patent CN)
Using the starting material Suo Feibuwei (crystal formation 1,1.04g) same with the crystallization process of embodiment 2, in adding 40mL water,
Magnetic agitation is simultaneously heated to 50 DEG C.And be stirred vigorously at 50 DEG C 1 hour, then add (0.1g) conduct of Suo Feibuwei crystal formations 6
Crystal seed, was cooled to 20 DEG C in 90 minutes, and insulated and stirred 16 hours has a large amount of white solids to separate out, and adheres to bottle wall.Exist afterwards
0~5 DEG C is cooled in 30 minutes and 2.5 hours are incubated, filtering for crystallizing mixture obtains the ice-cold water wash of filter cake 10mL, filter cake
With vacuum drying, vacuum -0.008MPa, it is dried 50 hours at 45 DEG C~50 DEG C, get Suo Feibuwei product 0.76g, yield：
76%, HPLC purity 99.33%, maximum single 0.25%.
Conclusion：Yield is substantially reduced than embodiment 2, when turning brilliant reaction, has a large amount of white solids to adhere to kettle wall, industrialization
During production, it is difficult to take out the product for adhering to reactor wall, be not suitable for industrialized production.And, this turn of brilliant reaction gained
Product HPLC purity is only 99.33%, and maximum list is miscellaneous to reach 0.25%；Not up to HPLC purity>99.5%, maximum list is miscellaneous to be less than
0.1% crude drug standard.
Comparative example 2：(with reference to the operating procedure of patent CN104829673A embodiment 1, not separating out crystal)
Using the starting material Suo Feibuwei (crystal formation 1,5g) same with the crystallization process of embodiment 2, it is added to equipped with 50mL rings
In the mixed solution of amyl methyl ether and 5mL methyl phenyl ethers anisoles, heating blends to 75 DEG C, and with 20 revs/min under stirring be solid
It is completely dissolved, takes about 15 minutes.It was cooled to 20~25 DEG C in 90 minutes afterwards, and adds the white powder of Suo Feibuwei crystal formations 6
Last (0.1g) is used as crystal seed.Stirred 16 hours with 30 revs/min of speed at this temperature, be then cooled to 0 DEG C and be incubated 1 hour,
Separate out without crystal.
Claims (10)
1. a kind of preparation method of Suo Feibuwei crystal formations 6, it is characterised in that it is comprised the following steps：By Suo Feibuwei crude products with contain
The solution that the alcohols solvent of water is formed, then mix with alkane, crystallize, obtain Suo Feibuwei crystal formations 6；Described Suo Feibuwei
Crude product is not more than 3% Suo Feibuwei crude products for the mass content of specific impurities II, and described mass content refers to specific impurities
The quality of II accounts for the percentage ratio of Suo Feibuwei crude product qualities；Described specific impurities II are Pentafluorophenol.
2. the preparation method of Suo Feibuwei crystal formations 6 as claimed in claim 1, it is characterised in that：
In the preparation method of described Suo Feibuwei crystal formations 6, in described " alcohols solvent containing water ", described water with it is described
The volume ratio of alcohols solvent be 0.02~0.05, described volume ratio refers to the volume of water and the volume of alcohols solvent
Ratio；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, in described " alcohols solvent containing water ", described " alcohols is molten
Agent " is one or more in methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, the tert-butyl alcohol and isobutanol；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described " aqueous alcohols solvent " is thick with described Suo Feibuwei
The volume mass ratio of product is 0.5mL/g~10.0mL/g；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described " Suo Feibuwei crude products and aqueous alcohols solvent formation
The temperature of solution " is 5 DEG C~65 DEG C；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described alkane be normal heptane, normal hexane, 2- hexanes, normal octane and
One or more in isobutyltrimethylmethane.；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described alkane is with the volume mass ratio of Suo Feibuwei crude products
3.0mL/g~50.0mL/g；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described Suo Feibuwei crude products are the crude product of Suo Feibuwei crystal formations 1, rope
The crude product of Fei Buwei crystal formations 2, the crude product of Suo Feibuwei crystal formations 3, the crude product of Suo Feibuwei crystal formations 4, the crude product of Suo Feibuwei crystal formations 5 and Suo Feibu
One or more in the unformed crude product of Wei.
3. the preparation method of Suo Feibuwei crystal formations 6 as claimed in claim 2, it is characterised in that：
In the preparation method of described Suo Feibuwei crystal formations 6, in described " alcohols solvent containing water ", described water with it is described
Alcohols solvent volume ratio be 0.02,0.03,0.04 or 0.05；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, in described " alcohols solvent containing water ", described " alcohols is molten
Agent " is one or more in ethanol, isopropanol, n-butyl alcohol, the tert-butyl alcohol and isobutanol；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described " aqueous alcohols solvent " is thick with described Suo Feibuwei
The volume mass ratio of product is 2.0mL/g~9.0mL/g；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described " Suo Feibuwei crude products and aqueous alcohols solvent formation
The temperature of solution " is 5 DEG C~50 DEG C；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described alkane is with the volume mass ratio of Suo Feibuwei crude products
5.0mL/g~45.0mL/g.
4. the preparation method of Suo Feibuwei crystal formations 6 as claimed in claim 3, it is characterised in that：
In the preparation method of described Suo Feibuwei crystal formations 6, described " aqueous alcohols solvent " is thick with described Suo Feibuwei
The volume mass ratio of product is 3.1mL/g, 3.2mL/L, 4.1mL/g, 4.2mL/g or 6.3mL/g；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described " Suo Feibuwei crude products and aqueous alcohols solvent formation
The temperature of solution " is 5 DEG C~10 DEG C, 10 DEG C~15 DEG C, 20 DEG C~25 DEG C, 40 DEG C~45 DEG C or 45 DEG C~50 DEG C；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described alkane is with the volume mass ratio of Suo Feibuwei crude products
6.0mL/g, 12.0mL/L, 13.0mL/g, 15.0mL/g, 20.0mL/g, 22.0mL/g, 30.0mL/g or 40.0mL/g.
5. the preparation method of Suo Feibuwei crystal formations 6 as claimed in claim 1, it is characterised in that：
In the preparation method of described Suo Feibuwei crystal formations 6, the mode of described mixing is Deca；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, described crystallize is carried out under agitation；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, the temperature of described crystallize is 0~50 DEG C；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, the time of described crystallize is 10 hours~96 hours.
6. the preparation method of Suo Feibuwei crystal formations 6 as claimed in claim 5, it is characterised in that：
In the preparation method of described Suo Feibuwei crystal formations 6, when being mixed by the way of Deca, the speed of described Deca is
1mL/min~100mL/min；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, when described crystallize is carried out under agitation, described stirring
Speed is 60 revs/min~500 revs/min；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, the temperature of described crystallize is 10 DEG C~35 DEG C；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, the time of described crystallize is 12 hours~48 hours.
7. the preparation method of Suo Feibuwei crystal formations 6 as claimed in claim 6, it is characterised in that：
In the preparation method of described Suo Feibuwei crystal formations 6, when being mixed by the way of Deca, the speed of described Deca is
1mL/min~80mL/min；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, when described crystallize is carried out under agitation, described stirring
Speed is 200 revs/min~260 revs/min；
And/or,
In the preparation method of described Suo Feibuwei crystal formations 6, time of described crystallize is 15 hours, 16 hours, 24 hours, 34
Hour, 36 hours or 44 hours.
8. the preparation method of Suo Feibuwei crystal formations 6 as claimed in claim 1, it is characterised in that：
In the preparation method of described Suo Feibuwei crystal formations 6, described " Suo Feibuwei crude products and aqueous alcohols solvent formation
Solution " is obtained using following steps：By Suo Feibuwei dissolving crude products in aqueous alcohols solvent, obtain Suo Feibuwei crude products with
The solution that aqueous alcohols solvent is formed；
And/or,
The preparation method of described Suo Feibuwei crystal formations 6, including following post-processing step：Suo Feibuwei crystal formations 6 are filtered, washed
Wash, be dried to obtain Suo Feibuwei crystal formations 6 after purification.
9. the preparation method of Suo Feibuwei crystal formations 6 as claimed in claim 8, it is characterised in that：
In the preparation method of described Suo Feibuwei crystal formations 6, described " Suo Feibuwei crude products and aqueous alcohols solvent formation
In the step of solution " is adopted, the temperature of described dissolving is 5 DEG C~65 DEG C；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, described filtration is using filter paper or filter cloth
Filter；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, the solvent that described washing is adopted is for alcohol
The mixed solvent or water of class solvent and alkane；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, the number of times of described washing is 1 time~3
It is secondary；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, described drying is vacuum drying；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, the temperature of described drying is 30 DEG C~
70℃；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, the time of described drying is 10 hours
~50 hours.
10. the preparation method of Suo Feibuwei crystal formations 6 as claimed in claim 9, it is characterised in that：
In the preparation method of described Suo Feibuwei crystal formations 6, described " Suo Feibuwei crude products and aqueous alcohols solvent formation
In the step of solution " is adopted, the temperature of described dissolving is 5 DEG C~50 DEG C；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, when being filtered using filter paper, described filter
Paper is Medium speed filter paper；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, when using filter-cloth filtering, described filter
Cloth is 200 mesh~300 mesh filter clothes；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, the solvent adopted when described washing for
During the mixed solvent of alcohols solvent and alkane, described alcohols solvent is methanol, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol, uncle
One or more in butanol and isobutanol；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, the solvent adopted when described washing for
During the mixed solvent of alcohols solvent and alkane, described alkane be the one kind in normal heptane, normal hexane, normal octane and isobutyltrimethylmethane. or
It is various；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, the solvent adopted when described washing for
During the mixed solvent of alcohols solvent and alkane, the alcohols solvent described in described the mixed solvent of alkane " alcohols solvent with " with
The volume ratio of described alkane is 5:1~1:5；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, when described drying is to be vacuum dried,
Described vacuum drying is carried out in vacuum drying oven；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, the temperature of described drying is 45 DEG C~
60℃；
And/or,
In the post-processing step that the preparation method of described Suo Feibuwei crystal formations 6 includes, the time of described drying is 16 hours
~30 hours.
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| 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 |
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| CN102858790A (en) * | 2010-03-31 | 2013-01-02 | 吉利德制药有限责任公司 | Nucleoside Phosphoramidates |
| WO2016023905A1 (en) * | 2014-08-13 | 2016-02-18 | Sandoz Ag | New and efficient process for the preparation of crystalline form 6 of sofosbuvir |
| 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 |
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| CN102858790A (en) * | 2010-03-31 | 2013-01-02 | 吉利德制药有限责任公司 | Nucleoside Phosphoramidates |
| WO2016023905A1 (en) * | 2014-08-13 | 2016-02-18 | Sandoz Ag | New and efficient process for the preparation of crystalline form 6 of sofosbuvir |
| 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 |
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| CN107490633A (en) * | 2017-07-21 | 2017-12-19 | 江苏工程职业技术学院 | A kind of method of genotoxicity impurity Pentafluorophenol in high performance liquid chromatography tandem mass spectrum combination detection Suo Feibuwei |
| 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 |
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