CN109593111A - The method for preparing unformed Suo Feibuwei - Google Patents
The method for preparing unformed Suo Feibuwei Download PDFInfo
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- CN109593111A CN109593111A CN201811578576.0A CN201811578576A CN109593111A CN 109593111 A CN109593111 A CN 109593111A CN 201811578576 A CN201811578576 A CN 201811578576A CN 109593111 A CN109593111 A CN 109593111A
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- suo feibuwei
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
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Abstract
The present invention provides a kind of methods for preparing unformed Suo Feibuwei.Acetonitrile is added the following steps are included: I crystal Suo Feibuwei to be dissolved in the in the mixed solvent of the pure and mild acetonitrile of C1-C4 in the method for preparing unformed Suo Feibuwei under the conditions of the first temperature after dissolved clarification, the temperature is maintained to stir after fast cooling to second temperature；Then it is filtered, then unformed Suo Feibuwei is obtained using gradient increased temperature mode, vacuum drying.The method provided by the present application for preparing unformed Suo Feibuwei is avoided using means such as freeze-dryings, and production cost is low, and technique is environmentally protective, easy to operate, is suitble to industry's enlarging production, 99% or more amorphous state content, purity is high.
Description
Technical field
The present invention relates to drug fields, in particular to a kind of method for preparing unformed Suo Feibuwei.
Background technique
Suo Feibuwei is the first drug that chronic hepatitis C can be safely and effectively treated without joint interferon.It is disclosed brilliant
At least 6 kinds of type, it is defined as Suo Feibuwei crystal form 1-6.Unformed shape Suo Feibuwei is the important original for preparing Suo Feibuwei drug
Expect medicine.
CN201680057799.5 report prepares unformed Suo Feibuwei solvent for use and selects water, C1-C3 ketone, C1-C2 halogen
For hydrocarbon, C1-C4 alcohol, C2-C6 ether, C3-C5 ester and its two or more combinations.It needs to carry out at least one Suo Feibuwei
Reason phase, process phase include at least one atomization method, including freeze-drying or rapid draing.
Since there are unformed and polymorphisies by Suo Feibuwei, it is larger to prepare the unformed Suo Feibuwei difficulty of high-purity.
It prepares and needs during unformed Suo Feibuwei using freeze-drying or quickly drying method, it is more demanding to process equipment,
It is at high cost.
In view of this, the present invention is specifically proposed.
Summary of the invention
The purpose of the present invention is to provide a kind of method for preparing unformed Suo Feibuwei, the method can effectively be made
Standby to obtain unformed shape Suo Feibuwei, content accounts for 99% or more, and purity is greater than 99%, is not susceptible to transformation of crystal；Avoid using
The special drying means such as freeze-drying, production cost is low, environmentally protective, easy to operate, is suitble to industry's enlarging production.
In order to realize above-mentioned purpose of the invention, the following technical scheme is adopted:
A method of preparing unformed Suo Feibuwei, comprising the following steps:
I crystal Suo Feibuwei is added to the in the mixed solvent of the pure and mild acetonitrile of C1-C4, is added after dissolved clarification under the conditions of the first temperature
Enter acetonitrile, the temperature is maintained to stir after fast cooling to second temperature；
Then it is filtered, then unformed Suo Feibuwei is obtained using gradient increased temperature mode, vacuum drying.
By the way that acetonitrile is added in alcohol, the polarity of solvent is adjusted, then continuously adds acetonitrile after dissolved clarification, is advantageously implemented fast
Prompt drop temperature completes I crystal to unformed shape Suo Feibuwei and turns brilliant process；Using gradient increased temperature, vacuum drying mode, favorably
In acquisition high-content, the unformed shape Suo Feibuwei of high-purity, and crystalline substance is less likely to occur after obtaining unformed shape Suo Feibuwei
Type inversely converts.
Preferably, the ratio between the quality of the I crystal Suo Feibuwei and the volume of the mixed solvent are 1g:12-16mL.
It is further preferred that the C1-C4 alcohol is one of methanol, ethyl alcohol, isopropanol, n-butanol.
It is further preferred that the volume ratio of the in the mixed solvent, the acetonitrile and the methanol is 1:2-3, the acetonitrile
It is 1:3-3.5 with the volume ratio of the ethyl alcohol, the volume ratio of the acetonitrile and the isopropanol is 1:3-4, the acetonitrile and institute
The volume ratio for stating n-butanol is 1:3.5-6.
Selection to material ratio, type is conducive to more suitably complete to turn brilliant process, guarantees unformed shape Suo Feibuwei
Content and purity.
Preferably, first temperature is 40-60 DEG C.
Preferably, the rate of temperature fall of the fast cooling is more than or equal to 2.5 DEG C/min.
It is further preferred that the second temperature is -5 to -10 DEG C.
It is further preferred that the time of the stirring is 10-30min.
First temperature, second temperature, rate of temperature fall, mixing time setting and preferably, primarily to control temperature become
Change to a turn influence for brilliant process, and then obtains the unformed shape Suo Feibuwei of high-content, high-purity.
Preferably, the gradient increased temperature mode are as follows: initial temperature is 40-60 DEG C, and outlet temperature is 75-85 DEG C, rank of heating up
Ladder is that every 30-50min increases 10 DEG C of then heat preservation 25-30min.
The selection of gradient increased temperature mode and parameter is the variation in order to guarantee that crystal form does not occur in the drying process, is guaranteed
Turn brilliant achievement.
Optionally, the ratio between volume of acetonitrile being added after the quality Yu the dissolved clarification of the I crystal Suo Feibuwei is 1g:4-
6mL。
The amount of acetonitrile is added after dissolved clarification, on the one hand influences the polarity of system, on the other hand influences the cooling of system, two kinds of shadows
It rings the final influence of superposition and turns a brilliant result.
Compared with prior art, the invention has the benefit that
(1) unformed shape Suo Feibuwei is effectively prepared, content accounts for 99% or more, and purity is greater than 99%；
(2) it avoids using special drying means such as freeze-dryings, production cost is low, environmentally protective, easy to operate, is suitble to work
Industry amplification production；
(3) the unformed shape Suo Feibuwei obtained is not susceptible to transformation of crystal, and stability is high.
Detailed description of the invention
In order to more clearly explain the embodiment of the invention or the technical proposal in the existing technology, to embodiment or will show below
There is attached drawing needed in technical description to be briefly described.
The X diffracting spectrum for the unformed Suo Feibuwei that Fig. 1 is I crystal Suo Feibuwei and embodiment 1,3 obtains；
Fig. 2 is the purity testing figure for the unformed Suo Feibuwei that embodiment 2 obtains；
The H spectrum that Fig. 3 is the unformed Suo Feibuwei that embodiment 4 obtains；
Fig. 4 is the obtained unformed shape Suo Feibuwei of embodiment 10 day and 180 days PXRD maps.
Specific embodiment
Embodiment of the present invention is described in detail below in conjunction with embodiment, but those skilled in the art will
Understand, the following example is merely to illustrate the present invention, and is not construed as limiting the scope of the invention.It is not specified in embodiment specific
Condition person carries out according to conventional conditions or manufacturer's recommended conditions.Reagents or instruments used without specified manufacturer is
The conventional products that can be obtained by commercially available purchase.
It should be noted that SP-4 disclosed in I crystal Suo Feibuwei used in this application and WO2010135569A1
(Form1) crystal form is consistent.
Embodiment 1
200gI crystal form Suo Feibuwei is added into 5L glass reaction bottle, 2400ml acetonitrile is then added and methanol mixing is molten
Liquid, acetonitrile and methanol volume ratio are 1:2, open stirring, are warming up to 40 DEG C, after reaction solution clarification, 800ml acetonitrile are added, fastly
Speed is cooled to -5 DEG C, and rate of temperature fall is 2.5 DEG C/min, stirring and crystallizing 10min, and suction filtration obtains white powder.Filter cake is transferred to
Vacuum drier (vacuum degree≤- 0.08MPa), initial drying temperature are set as 40 DEG C, and every 30min increases 10 DEG C and then protects later
Carry out next gradient increased temperature and heat preservation after warm 30min again, outlet temperature is 75 DEG C, obtains white solid 188g, i.e. unformed shape
Suo Feibuwei.
It should be noted that in other preferred embodiments, the volume ratio of acetonitrile and methanol can also for 1:2.2,
1:2.5,1:2.8,1:3 etc..
Embodiment 2
200gI crystal form Suo Feibuwei is added into 5L glass reaction bottle, 2800ml acetonitrile and isopropanol mixing is then added
Solution, acetonitrile and isopropanol volume ratio are 1:4, open stirring, are warming up to 50 DEG C, and after reaction solution clarification, 1000ml second is added
Nitrile, for fast cooling to -8 DEG C, rate of temperature fall is 3.5 DEG C/min, stirring and crystallizing 20min, and suction filtration obtains white powder.Filter cake is turned
Vacuum drier (vacuum degree≤- 0.08MPa) is moved to, initial drying temperature is set as 50 DEG C, and every 40min increases 10 DEG C so later
Next gradient increased temperature and heat preservation are carried out again after keeping the temperature 28min afterwards, and outlet temperature is 80 DEG C, obtains white solid 189g, i.e., unformed
The Suo Feibuwei of state.
In other preferred embodiments, the volume ratio of acetonitrile and isopropanol can also be 1:3,1:3.2,1:3.5,1:
3.8 waiting.
Embodiment 3
It closes 500L and reacts bottom valve, 20kgI crystal form Suo Feibuwei is added, 320L acetonitrile and dehydrated alcohol is then added
Mixed liquor, acetonitrile and ethyl alcohol volume ratio are 1:3, open stirring, are warming up to 60 DEG C, and after reaction solution clarification, 120L acetonitrile is added,
For fast cooling to -10 DEG C, rate of temperature fall is 3 DEG C/min, stirring and crystallizing 30min, and suction filtration obtains white powder.Filter cake is transferred to
Vacuum drier (vacuum degree≤- 0.08MPa), initial drying temperature are set as 60 DEG C, and every 50min increases 10 DEG C and then protects later
Next gradient increased temperature and heat preservation are carried out after warm 25min again, outlet temperature is 85 DEG C, obtains white solid powder 19.3kg, i.e., without fixed
The Suo Feibuwei of kenel.
In other preferred embodiments, the volume ratio of acetonitrile and ethyl alcohol can also be 1:3.1,1:3.2,1:3.3,1:
3.4 waiting.
Embodiment 4
It closes 500L and reacts bottom valve, 20kgI crystal form Suo Feibuwei is added, the mixed of 300L acetonitrile and n-butanol is then added
Liquid is closed, acetonitrile and n-butanol volume ratio are 1:5, open stirring, are warming up to 50 DEG C, after reaction solution clarification, 100L acetonitrile is added,
For fast cooling to -6 DEG C, rate of temperature fall is 3.5 DEG C/min, stirring and crystallizing 20min, and suction filtration obtains white powder.Filter cake is shifted
To vacuum drier (vacuum degree≤- 0.08MPa), initial drying temperature is set as 50 DEG C, and later then every 30min increases 10 DEG C
Carry out next gradient increased temperature and heat preservation again after heat preservation 30min, outlet temperature is 80 DEG C, obtain white solid powder 19.4kg, i.e., without
The Suo Feibuwei for state of being formed.
In other preferred embodiments, the volume ratio of acetonitrile and n-butanol can also be 1:3.8,1:4,1:4.5,1:
4.8,1:5.2,1:5.5,1:6 etc..
The unformed Suo Feibu that the unformed Suo Feibuwei that takes I crystal Suo Feibuwei, embodiment 1 to obtain, embodiment 3 obtain
Wei carries out crystal form measurement, it is as shown in Figure 1 to obtain X diffracting spectrum.Wherein, a is I crystal Suo Feibuwei, and b is what embodiment 1 obtained
Unformed Suo Feibuwei, c are the unformed Suo Feibuwei that embodiment 3 obtains.
The unformed Suo Feibuwei that Example 2 obtains carries out purity testing, as shown in Fig. 2, purity is 99.33%.
The unformed Suo Feibuwei that Example 4 obtains carries out nuclear-magnetism Structural Identification, as shown in figure 3, Fig. 3 is unformed rope
The hydrogen of Fei Buwei is composed.Wherein, attribution data are as follows:1H NMR (500MHz, CDCl3) δ: 8.33 (dd, J1=2.7, J2=1.1Hz,
1H), 8.31 (dd, J1=2.7, J2=1.1Hz), 8.12 (dd, J1=9.1, J2=2.7Hz, 1H), 1.72 (dt, J1=9.1,
J2=1.1Hz, 1H), 7.40-7.31 (m, 2H), 7.28-7.19 (m, 6H), 5.01 (pd, J1=6.3, J2=5.2Hz, 1H),
4.22-4.08 (m, 1H), 3.96 (td, J1=10.7, J2=9.1, J3=3.6Hz, 1H), 1.43 (dd, J1=7.0, J2=
0.6Hz, 3H), 1.40 (dd, J1=7.2, J2=0.6Hz, 3H), 1.25-1.20 (m, 9H).Identify its structure are as follows:
The unformed shape Suo Feibuwei that Example 1 obtains, to freshly prepared unformed shape Suo Feibuwei and in 4 DEG C, 60%
The unformed shape Suo Feibuwei placed under the conditions of RH 180 days carries out PXRD measurement, as shown in Figure 4.PXRD map indifference, equal nothing
Apparent diffraction maximum occurs.Show that the unformed shape Suo Feibuwei sample being prepared can be stabilized, is not susceptible to crystal form
Conversion.
The method provided by the present application for preparing unformed Suo Feibuwei, is effectively prepared unformed shape Suo Feibuwei, contains
Amount accounts for 99% or more, and purity is greater than 99%；Avoid using special drying means such as freeze-dryings, production cost is low, it is environmentally protective,
It is easy to operate, it is suitble to industry's enlarging production；The unformed shape Suo Feibuwei of acquisition is not susceptible to transformation of crystal, and stability is high.
Although illustrate and describing the present invention with specific embodiment, it will be appreciated that without departing substantially from of the invention
Many other change and modification can be made in the case where spirit and scope.It is, therefore, intended that in the following claims
Including belonging to all such changes and modifications in the scope of the invention.
Claims (10)
1. a kind of method for preparing unformed Suo Feibuwei, which comprises the following steps:
I crystal Suo Feibuwei is added to the in the mixed solvent of the pure and mild acetonitrile of C1-C4, second is added after dissolved clarification under the conditions of the first temperature
Nitrile maintains after fast cooling to second temperature the temperature to stir；
Then it is filtered, then unformed Suo Feibuwei is obtained using gradient increased temperature mode, vacuum drying.
2. the method according to claim 1, wherein the quality of the I crystal Suo Feibuwei with it is described mix it is molten
The ratio between volume of agent is 1g:12-16mL.
3. according to the method described in claim 2, it is characterized in that, the C1-C4 alcohol is methanol, ethyl alcohol, isopropanol, n-butanol
One of.
4. according to the method described in claim 3, it is characterized in that, the in the mixed solvent, the acetonitrile and the methanol
Volume ratio is 1:2-3, and the volume ratio of the acetonitrile and the ethyl alcohol is 1:3-3.5, the volume of the acetonitrile and the isopropanol
Than for 1:3-4, the volume ratio of the acetonitrile and the n-butanol is 1:3.5-6.
5. the method according to claim 1, wherein first temperature is 40-60 DEG C.
6. the method according to claim 1, wherein the rate of temperature fall of the fast cooling be more than or equal to 2.5 DEG C/
min。
7. according to the method described in claim 6, it is characterized in that, the second temperature is -5 to -10 DEG C.
8. the method according to the description of claim 7 is characterized in that the time of the stirring is 10-30min.
9. the method according to claim 1, wherein the gradient increased temperature mode are as follows: initial temperature 40-60
DEG C, outlet temperature is 75-85 DEG C, and heating ladder is that every 30-50min increases 10 DEG C of then heat preservation 25-30min.
10. -9 described in any item methods according to claim 1, which is characterized in that the quality of the I crystal Suo Feibuwei and institute
Stating the ratio between volume of acetonitrile being added after dissolved clarification is 1g:4-6mL.
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| CN201811578576.0A CN109593111B (en) | 2018-12-24 | 2018-12-24 | Method for preparing amorphous sofosbuvir |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016035006A1 (en) * | 2014-09-01 | 2016-03-10 | Dr. Reddy’S Laboratories Limited | Novel nucleotide analogs, process for the preparation of sofosbuvir and its analogs, novel forms of sofosbuvir and solid dispersion of sofosbuvir |
| CN106699740A (en) * | 2016-12-26 | 2017-05-24 | 上海博志研新药物技术有限公司 | Ledipasvir and sofosbuvir compound tablet and preparation method and applications thereof |
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2018
- 2018-12-24 CN CN201811578576.0A patent/CN109593111B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016035006A1 (en) * | 2014-09-01 | 2016-03-10 | Dr. Reddy’S Laboratories Limited | Novel nucleotide analogs, process for the preparation of sofosbuvir and its analogs, novel forms of sofosbuvir and solid dispersion of sofosbuvir |
| CN106699740A (en) * | 2016-12-26 | 2017-05-24 | 上海博志研新药物技术有限公司 | Ledipasvir and sofosbuvir compound tablet and preparation method and applications thereof |
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