CN108976168A - A kind of half calcium salt novel crystal forms of Pitavastatin and preparation method thereof - Google Patents
A kind of half calcium salt novel crystal forms of Pitavastatin and preparation method thereof Download PDFInfo
- Publication number
- CN108976168A CN108976168A CN201710406204.9A CN201710406204A CN108976168A CN 108976168 A CN108976168 A CN 108976168A CN 201710406204 A CN201710406204 A CN 201710406204A CN 108976168 A CN108976168 A CN 108976168A
- Authority
- CN
- China
- Prior art keywords
- pitavastatin
- calcium salt
- crystal forms
- novel crystal
- half calcium
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of half calcium salt novel crystal forms of Pitavastatin, it is named as crystal form I, the half calcium salt novel crystal forms of Pitavastatin are in the X-ray powder diffraction collection that Cu-K alpha ray is measured, and include at least following characteristics peak: 2 θ value of the angle of diffraction is 4.56 ± 0.1 °, 5.10 ± 0.1 °, 6.74 ± 0.1 °, 6.94 ± 0.1 °, 9.12 ± 0.1 °, 10.32 ± 0.1 °, 11.32 ± 0.1 °, 13.72 ± 0.1 ° and 21.24 ± 0.1 °；The water content of the crystal form is 2~5%.The present invention also provides the preparation method of the half calcium salt novel crystal forms of Pitavastatin, simplicity, high income, favorable reproducibility, resulting novel crystal forms purity is high, stability are good, are suitable for industrialized production.
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to the crystal form of medical compounds more particularly to a kind of Pitavastatin
The novel crystal forms and preparation method thereof of half calcium salt.
Background technique
Half calcium salt of Pitavastatin, chemical name are as follows: [(3R, 5S, 6E) -7- (2- cyclopropyl -4- (4- fluorophenyl) -3- quinoline
Base) -3,5- dihydroxy -6- heptenoic acid] half calcium salt, structural formula is shown below:
First fully synthetic selectivity that half calcium salt of Pitavastatin is developed by Japanese chemical company and Kowa company Ltd,
Competitive 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor, in November, 1999 in Japan registration, and
It is fat-reducing medicament most potent so far on July 17th, 2003 for the first time in Japan's approval listing.
Patent WO 2004/072040 provides half calcium salt of Pitavastatin, and there are polymorphous phenomenons, and disclose and cut down
Half calcium salt crystal form of statin: A, B, C, D, E, F and unformed.102321019 A of patent CN reports half calcium salt crystal form of Pitavastatin
The water content of A is 5~15%, in the X-ray powder diffraction spectrum that it is measured using CuK alpha ray, in the angle of diffraction (2 θ)
The peak for thering is a relative intensity to be greater than 25% for 30.16 °.It is brilliant that patent US9034901B2 discloses a kind of half calcium salt of Pitavastatin
Type, since the crystal form is to be 8~12% half calcium salt of Pitavastatin by first preparing water content, then be dried under reduced pressure so that its is aqueous
Amount is less than 5%, and therefore, unformed content is much larger than crystal type in crystal form described in the patent.101195603 A of CN is disclosed
A kind of crystal form and preparation method thereof that half calcium salt of Pitavastatin is new, the water content of the novel crystal forms are 0.5~3%.WO 2012/
Half calcium salt of Pitavastatin disclosed in 063254 Al is crystal form H1.
The preparation of usually report half calcium salt of Pitavastatin is added in the sodium-salt aqueous solution of Pitavastatin carboxylic acid
Calcium chloride water forms half calcium precipitation of Pitavastatin, then isolates and purifies to obtain product.But because half calcium salt of Pitavastatin is in water
Solubility is extremely low in solution, and Precipitation is immediately generated after reaction, causes the product particle generated tiny, is easy conglomerate,
And carry impurity secretly.For this purpose, 102653523 A of patent CN improves method, disclose by being solvent body in tetrahydrofuran-water
The recrystallization of system makes the purity for improving half calcium salt of Pitavastatin, however, the HPLC purity that this method obtains product also only has 98%
Left and right.
In view of the pharmacy value of half calcium salt of Pitavastatin, him is cut down to obtain purity is high, preparing simple and favorable reproducibility
The different crystal forms of half calcium salt of spit of fland are of great significance.
Summary of the invention
Technical problem to be solved by the present invention lies in above-mentioned shortcoming is overcome, provide a kind of stability it is good, it is with high purity,
Favorable reproducibility, the half calcium salt novel crystal forms of Pitavastatin and preparation method for being suitble to industrialized production.
The present inventor surprisingly has found a kind of half calcium of Pitavastatin in the research of half calcium salt crystallization process of Pitavastatin
The novel crystal forms of salt, and preparation method is easy, and purity is high, stability is good, is suitable for further research and development.The reproduction of the novel crystal forms
Property it is good, and stability is good, purity is high.Compared with the prior art, it especially improves a lot in terms of purity.
The present invention provides a kind of half calcium salt novel crystal forms of Pitavastatin, are named as crystal form I；
It is included at least following characteristics peak: spread out in the X-ray powder diffraction collection being measured using Cu-K alpha ray
2 θ value of firing angle be 4.56 ± 0.1 °, 5.10 ± 0.1 °, 6.74 ± 0.1 °, 6.94 ± 0.1 °, 9.12 ± 0.1 °, 10.32 ± 0.1 °,
11.32 ± 0.1 °, 13.72 ± 0.1 ° and 21.24 ± 0.1 °.
Preferably, the half calcium salt novel crystal forms of Pitavastatin, in the X-ray powder being measured using Cu-K alpha ray
In last diffracting spectrum, include at least following characteristics peak: its 2 θ angle value and relative intensity are as shown in table 1 below:
Table 1
X-ray powder diffraction pattern (or characteristic peak) significant difference of half calcium salt novel crystal forms of Pitavastatin of the present invention
In existing known crystal form.For example, there are 4.56 °, 6.74 °, 6.94 ° of characteristic peaks in novel crystal forms of the invention, and at existing
It cuts down and does not have this 3 characteristic peaks in half calcium salt crystal form A of statin.6.2 ° and 7.7 ° of feature is not present in novel crystal forms of the invention
Peak, and then exist in existing half calcium salt crystal form B of Pitavastatin.It is not present in the novel crystal forms of half calcium salt of Pitavastatin of the present invention
9.6 ° and 13.0 ° of characteristic peak, and then there are this 2 characteristic peaks in existing half calcium salt crystal form F of Pitavastatin.Of the invention
Cut down in half calcium salt novel crystal forms of statin that there is no 4.3 °, 8.6 °, 13.1 ° of characteristic peaks, and disclosed in patent CN 101195603A
There are this 3 characteristic peaks in half calcium salt crystal form of Pitavastatin, and the water content of the crystal form is 0.5%~3%.Of the invention
It cuts down there is no 19.6 ° of characteristic peak in half calcium salt novel crystal forms of statin, still, there are 19.6 ° in crystal form disclosed in US9034901B2
Characteristic peak, and this characteristic peak be the crystal form the last the second peak；In addition, the characteristic peak of crystal form disclosed in US9034901B2 is opposite
Intensity and the characteristic peak relative intensity difference of crystal form of the invention are obvious, and the appearance position difference at main strong peak is significant.
Therefore, in a specific embodiment of the invention, the half calcium salt novel crystal forms of Pitavastatin are using Cu-K
In the X-ray powder diffraction collection that alpha ray is measured, at least following 2 θ of the angle of diffraction be 4.3 ± 0.1 °, 6.2 ± 0.1 °,
No characteristic peak at 7.7 ± 0.1 °, 8.6 ± 0.1 °, 9.6 ± 0.1 °, 13.0 ± 0.1 °, 13.1 ± 0.1 ° and 19.6 ± 0.1 °.
It is particularly preferred that the half calcium salt novel crystal forms of Pitavastatin have X-ray powder diffraction figure as shown in Figure 1
Spectrum.
Further, the half calcium salt novel crystal forms of Pitavastatin can be characterized by heat analysis.Described is cut down him
The typical DSC figure of half calcium salt novel crystal forms of spit of fland is shown in Fig. 3.It is characterized in that being included at 30 DEG C~100 DEG C has endothermic peak (peak
About 55 DEG C of top value), and have melting endothermic peak (about 200 DEG C of summit value) at 180 DEG C~210 DEG C；By common sense in the field, DSC
The error of test is also considered into, the error that the measurement of usual summit value allows to have ± 1 DEG C.Based on multiple batches of
The TGA test for cutting down half calcium salt novel crystal forms of statin, determines novel crystal forms of the invention when from room temperature to the temperature-rise period of 150 DEG C of ranges
In, there is about 2~5% thermal weight loss, shows that the water content of the half calcium salt crystal form of Pitavastatin is about 2~5%.Described is cut down
The typical TGA figure of half calcium salt novel crystal forms of statin shows in from room temperature to the temperature-rise period of 150 DEG C of ranges, have in Fig. 2
4.4% thermal weight loss.
Further, the half calcium salt novel crystal forms of Pitavastatin, which have, is included in 798 ± 2cm-1、919±2cm-1、
1028±2cm-1、1137±2cm-1、1193±2cm-1、1376±2cm-1、1412±2cm-1、1449±2cm-1、1564±
2cm-1、1611±2cm-1、1658±2cm-1、3011±2cm-1、3068±2cm-1Wave number peak Raman spectrum.
Preferably, the novel crystal forms of half calcium salt of Pitavastatin have Raman spectrogram as shown in Figure 4.
It is a further object of the present invention to provide the preparation sides of the novel crystal forms crystal form I of half calcium salt of Pitavastatin a kind of
Method, this method comprises: Pitavastatin sodium salt and water-soluble Ca salt are in containing aqueous solution of the methyl tertiary butyl ether(MTBE) as cosolvent
Reacted, crystallize, separate solid, be dried under reduced pressure to get.
The water-soluble Ca salt can be water-soluble Ca salt commonly used in the art, be selected from calcium chloride, calcium acetate or lactic acid
Calcium etc..
Preferably, " the containing aqueous solution of the methyl tertiary butyl ether(MTBE) as cosolvent " refer to containing volumetric concentration be 1~
The aqueous solution of 10% methyl tertiary butyl ether(MTBE).
It is highly preferred that " the containing aqueous solution of the methyl tertiary butyl ether(MTBE) as cosolvent " refers to that containing volumetric concentration be 1
The aqueous solution of~5% methyl tertiary butyl ether(MTBE).
The dosage of the aqueous solution is generally 5-50 times of Pitavastatin sodium salt quality, preferably at 5-30 times.
Preferably, pH value of reaction system is adjusted in the reaction 8~9, can be cut down in this way with the acquisition of higher reaction yield
Half calcium salt of statin.The adjusting of pH value is more preferably carried out using acetic acid.
Crystallization temperature is not particularly limited, generally in -5 DEG C to 50 DEG C ranges, preferably 0 DEG C to 40 DEG C, more preferably in 10-20
DEG C range.
Crystallization time is not particularly limited, but typically about 30 minutes to 24 hours.
As method for crystallising, it can be standing and crystallized, or can also be crystallized under stiring.It is preferred that stirring
Under crystallized.
In the present invention, " crystal form " word is not only interpreted as " crystal type " or " crystal structure "；It is " brilliant in technical solution
Type " is more interpreted as " substance with specific crystal structure " or " crystal of particular crystal type ".For example, in technical solution,
" crystal form of half calcium salt of Pitavastatin " can be understood as " half calcium salt of Pitavastatin with specific crystal structure " or " particular crystal
The crystal of half calcium salt of Pitavastatin of type ".
In the present invention, " novel crystal forms " characterization of the X-ray diffractogram by shown in is confirmed.Those skilled in the art's energy
Enough to understand, experimental error therein depends on condition, the preparation of sample and the purity of sample of instrument.In particular, this field skill
Known in art personnel, X-ray diffractogram would generally be changed with the condition of instrument.In addition, the experimental error of peak angle degree is logical
Often 5% or less, the error of these angles should also be considered into, allow generally for ± 0.1 ° of error.In addition, due to
The influence of the empirical factors such as height of specimen will cause the overall offset of peak angle degree, allow generally for certain offset.Thus, ability
Field technique personnel are it is understood that any belong to the crystal form with the same or similar figure of characteristic peak in map of the present invention
Within scope of the invention.
The positive effect of the present invention is:
Compared with the prior art, half calcium salt novel crystal forms stability of Pitavastatin provided by the invention is good, purity have it is very big
It improves, there is preferable medical value, and its purity in the prolonged storage period in December, stability of crystal form are preferable.
The preparation method of half calcium salt novel crystal forms of Pitavastatin of the present invention is easy to operate, and favorable reproducibility, high income is suitable for industrialized production,
There is biggish application value.
Detailed description of the invention
Fig. 1 is X-ray powder diffraction (PXRD) figure of half calcium salt novel crystal forms of Pitavastatin
Ordinate is 2 θ (°) of the angle of diffraction
Abscissa is relative intensity (CPS)
Fig. 2 is thermogravimetric analysis (TG) figure of the half calcium salt novel crystal forms of Pitavastatin of embodiment 2
Ordinate is temperature (DEG C)
Abscissa is weight (%)
Fig. 3 is differential scanning analysis (DSC) figure of half calcium salt novel crystal forms of Pitavastatin
Ordinate is temperature (DEG C)
Abscissa is hot-fluid (W/g)
Fig. 4 is Raman spectrum (Raman) figure of half calcium salt novel crystal forms of Pitavastatin
Ordinate is Raman shift (cm-1)
Abscissa is relative intensity (counts)
Specific embodiment
Polymorph in pharmaceuticals structure is detected in the present invention and the instrument of performance is as follows:
Powder x-ray diffraction (XRD) characterization: instrument: Rigaku D/Max-2550PC, CuK α radiation, power 40kV ×
250mA, 3~40 ° of 2 θ of scanning range, 0.02 ° of step width (step width), 5 °/min of scanning speed.
Thermogravimetric analysis (TG) characterization: instrument: TA company SDT Q600, purge gass: nitrogen 120ml/min, heating rate: 10
DEG C/min, temperature range: room temperature~380 DEG C.
Differential scanning calorimetric analysis (DSC) characterization: instrument: TA company DSC Q100, purge gass: nitrogen 50ml/min rises
Warm speed: 10 DEG C/min, temperature range: room temperature~230 DEG C.
Raman spectrum (Raman) characterization: instrument: Horiba company LabRAMHR Evolution, optical maser wavelength 633nm,
Laser power 100%, firing time 30s add up testing time 2 times, grating 600gr/mm.
The preparation of 1 Pitavastatin of embodiment, half calcium salt novel crystal forms (crystal form I)
The 5g Pitavastatin tert-butyl ester is suspended in 25ml water, stirs 0.5h, obtains suspension, instills 5.25ml 3mol/
The NaOH aqueous solution of L, stirs 4h at 50 DEG C, obtains homogeneous transparent solution, filtering.20ml water and 2ml methyl- tert is then added
Butyl ether stirs evenly.Be added dropwise 1.2g calcium acetate 10ml purification of aqueous solutions, be added dropwise, continue stir 4h, filter, and with fit
Amount purifying water washing, is dried under reduced pressure at 50 DEG C, obtains half calcium salt novel crystal forms of Pitavastatin.It is with X-ray powder shown in FIG. 1
Last diffraction pattern.The thermogravimetric analysis of the novel crystal forms of acquisition further discloses its water content about 4.7%.Differential scanning calorimetric analysis is taken off
Show about 200 DEG C of fusing point (see Fig. 3).The Raman spectrum of novel crystal forms is shown in Fig. 4.Confirmation is crystal form I；Yield is 90%, HPLC purity
It is 99.92%.
The preparation of 2 Pitavastatin of embodiment, half calcium salt novel crystal forms (crystal form I)
The 5g Pitavastatin tert-butyl ester is suspended in 20ml water, stirs 0.5h, obtains suspension, instills 5.25ml 3mol/
The NaOH aqueous solution of L, stirs 4h at 50 DEG C, obtains homogeneous transparent solution, filtering.2ml methyl tertiary butyl ether(MTBE) is then added to stir
It mixes uniformly, and adjusts pH value of solution to 8~9 with acetic acid.The 10ml purification of aqueous solutions of 1.2g calcium acetate is added dropwise, is added dropwise, continues
4h is stirred, is filtered, and purifies water washing with appropriate, is dried under reduced pressure at 50 DEG C, obtains half calcium salt novel crystal forms of Pitavastatin.It has
X-ray powder diffraction figure sample shown in FIG. 1.The thermogravimetric analysis of the novel crystal forms of acquisition further discloses its water content about 4.4%
(see Fig. 2).Confirmation is crystal form I；Yield is that 93%, HPLC purity is 99.91%.
The preparation of 3 Pitavastatin of embodiment, half calcium salt novel crystal forms (crystal form I)
The 5g Pitavastatin tert-butyl ester is suspended in 25ml water, stirs 0.5h, obtains suspension, instills 5.25ml 3mol/
The NaOH aqueous solution of L, stirs 4h at 50 DEG C, obtains homogeneous transparent solution, filtering.70ml water and 2ml methyl- tert is then added
Butyl ether stirs evenly.Be added dropwise 1.2g calcium acetate 10ml purification of aqueous solutions, be added dropwise, continue stir 4h, filter, and with fit
Amount purifying water washing, is dried under reduced pressure at 50 DEG C, obtains half calcium salt novel crystal forms of Pitavastatin.It is with X-ray powder shown in FIG. 1
Last diffraction pattern.The thermogravimetric analysis of the novel crystal forms of acquisition further discloses its water content about 2.3%.Confirmation is crystal form I；Yield is
88%, HPLC purity are 99.94%.
The preparation of 4 Pitavastatin of embodiment, half calcium salt novel crystal forms (crystal form I)
The 2kg Pitavastatin tert-butyl ester is suspended in 10L water, stirs 0.5h, obtains suspension, instills 2.1L 3mol/L
NaOH aqueous solution, stir 4h at 50 DEG C, obtain homogeneous transparent solution, filter.10L water and 80ml methyl- tert fourth is then added
Base ether stirs evenly.Be added dropwise 480g calcium acetate 4L purification of aqueous solutions, be added dropwise, continue stir 1h, filter, and in right amount it is pure
Change water washing, is dried under reduced pressure at 50 DEG C, obtains half calcium salt novel crystal forms of Pitavastatin.It spreads out with X-ray powder shown in FIG. 1
Penetrate pattern.The thermogravimetric analysis of the novel crystal forms of acquisition further discloses its water content about 2.3%.Confirmation is crystal form I；Yield is
90%, HPLC purity are 99.93%.
The preparation of 5 Pitavastatin of embodiment, half calcium salt novel crystal forms (crystal form I)
The 2kg Pitavastatin tert-butyl ester is suspended in 10L water, stirs 0.5h, obtains suspension, instills 2.1L 3mol/L
NaOH aqueous solution, stir 4h at 50 DEG C, obtain homogeneous transparent solution, filter.10L water and 50ml methyl- tert fourth is then added
Base ether stirs evenly, and adjusts pH value of solution to 8~9 with acetic acid.The 4L purification of aqueous solutions of 480g calcium acetate is added dropwise, is added dropwise,
Continue to stir 2h, filter, and purify water washing with appropriate, is dried under reduced pressure at 50 DEG C, obtains half calcium salt novel crystal forms of Pitavastatin.Its
With X-ray powder diffraction figure sample shown in FIG. 1.The thermogravimetric analysis of the novel crystal forms of acquisition further discloses its water content about
2.1%.Confirmation is crystal form I；Yield is that 93%, HPLC purity is 99.91%.
The long-time stability data of the sample are as shown in table 2.
The test result of 2 Pitavastatin of table, half calcium salt novel crystal forms long-time stability
(30 ± 2 DEG C of temperature, humidity 75 ± 5%)
Comparative example 1
According to 102321019 A the method for Nissan Chemical Ind Ltd patent application CN, Pitavastatin half is prepared
Calcium salt crystal form A.
The 5g Pitavastatin tert-butyl ester is dissolved in 92.2g ethyl alcohol, stirring and dissolving, 107.9g water is added.It is cooled to -3 DEG C
To 3 DEG C, the NaOH solution that 6.22ml concentration is 2mol/l is added dropwise, stirs 4h at the same temperature, completes hydrolysis.Decompression is steamed
Distillation solvent adjusts internal temperature to 10-20 DEG C, the calcium acetate solution being prepared separately is added dropwise after removing 110g ethanol/water
(2.2g calcium acetate is dissolved in 7.2g water).12h is stirred at same temperature after being added dropwise to complete, is filtered, after being rinsed with water, at 40 DEG C
Under be dried under reduced pressure, until water content be 9.4%.
Crystal form A, the HPLC purity that product proves half calcium salt of Pitavastatin through X-ray powder diffraction is 98.80%.
Conclusion: the purity for half calcium salt of Pitavastatin that the present invention obtains is substantially better than this method, and this method preparation is time-consuming
It is longer.
Claims (10)
1. a kind of half calcium salt novel crystal forms of Pitavastatin, which is characterized in that the half calcium salt novel crystal forms of Pitavastatin are crystal form I,
In the X-ray powder diffraction collection that Cu-K alpha ray is measured, include at least following characteristics peak: 2 θ value of the angle of diffraction be 4.56 ±
0.1°、5.10±0.1°、6.74±0.1°、6.94±0.1°、9.12±0.1°、10.32±0.1°、11.32±0.1°、
13.72 ± 0.1 ° and 21.24 ± 0.1 °.
2. half calcium salt novel crystal forms of Pitavastatin according to claim 1, which is characterized in that half calcium salt of Pitavastatin
Novel crystal forms include at least following characteristics peak, 2 θ angle values in the X-ray powder diffraction collection that Cu-K alpha ray is measured
And relative intensity is as follows:
3. half calcium salt novel crystal forms of Pitavastatin according to claim 1 or 2, which is characterized in that the Pitavastatin half
The DSC of calcium salt novel crystal forms schemes, and has endothermic peak at 30 DEG C~100 DEG C, has melting endothermic peak at 180 DEG C~210 DEG C.
4. half calcium salt novel crystal forms of Pitavastatin according to claim 1 or 2, which is characterized in that the Pitavastatin half
Calcium salt novel crystal forms have 2~5% thermal weight losses in the TGA test from room temperature to the temperature-rise period of 150 DEG C of ranges.
5. half calcium salt novel crystal forms of Pitavastatin according to claim 1 or 2, which is characterized in that the Pitavastatin half
The Raman spectrogram that there is calcium salt novel crystal forms Fig. 4 to show, the peak comprising following wave number: 798 ± 2cm-1、919±2cm-1、1028
±2cm-1、1137±2cm-1、1193±2cm-1、1376±2cm-1、1412±2cm-1、1449±2cm-1、1564±2cm-1、
1611±2cm-1、1658±2cm-1、3011±2cm-1With 3068 ± 2cm-1。
6. a kind of preparation method of the described in any item half calcium salt novel crystal forms of Pitavastatin of claim 1-5, which is characterized in that should
Method includes: that Pitavastatin sodium salt and water-soluble Ca salt carry out instead in containing aqueous solution of the methyl tertiary butyl ether(MTBE) as cosolvent
It answers, crystallizes, separate solid, be dried under reduced pressure to get half calcium salt crystal form I of Pitavastatin.
7. the preparation method of half calcium salt novel crystal forms of Pitavastatin according to claim 6, which is characterized in that the water solubility
Calcium salt is selected from calcium chloride, calcium acetate or calcium lactate.
8. the preparation method of half calcium salt novel crystal forms of Pitavastatin according to claim 6, which is characterized in that described contains
Methyl tertiary butyl ether(MTBE) is the aqueous solution for being 1~10% methyl tertiary butyl ether(MTBE) containing volumetric concentration as the aqueous solution of cosolvent；Institute
The dosage for stating aqueous solution is 5-50 times of Pitavastatin sodium salt quality；And/or it adjusts pH value of reaction system and is adjusted to 8~9.
9. the preparation method of half calcium salt novel crystal forms of Pitavastatin according to claim 8, which is characterized in that described contains
Methyl tertiary butyl ether(MTBE) is the aqueous solution for being 1~5% methyl tertiary butyl ether(MTBE) containing volumetric concentration as the aqueous solution of cosolvent；It is described
The dosage of aqueous solution is 5-30 times of Pitavastatin sodium salt quality；And/or reaction system vinegar acid for adjusting pH value.
10. the preparation method of half calcium salt novel crystal forms of Pitavastatin according to claim 6, which is characterized in that the crystallization
Temperature be -5 DEG C to 50 DEG C ranges, preferably 0 DEG C to 40 DEG C, more preferably in 10-20 DEG C of range；Crystallization time is 30 minutes to 24 small
When；Method for crystallising is selected to stand and crystallize or crystallized under stiring.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710406204.9A CN108976168B (en) | 2017-06-02 | 2017-06-02 | Pitavastatin semi-calcium salt crystal form and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710406204.9A CN108976168B (en) | 2017-06-02 | 2017-06-02 | Pitavastatin semi-calcium salt crystal form and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108976168A true CN108976168A (en) | 2018-12-11 |
| CN108976168B CN108976168B (en) | 2020-09-25 |
Family
ID=64501870
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710406204.9A Active CN108976168B (en) | 2017-06-02 | 2017-06-02 | Pitavastatin semi-calcium salt crystal form and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108976168B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109053568A (en) * | 2018-08-29 | 2018-12-21 | 南京卓康医药科技有限公司 | A kind of high-purity Pitavastatin Calcium novel crystal forms and preparation method thereof |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1625550A (en) * | 2002-01-28 | 2005-06-08 | 诺瓦提斯公司 | Process for the manufacture of organic compounds |
| CN1876633A (en) * | 2005-06-10 | 2006-12-13 | 上海药明康德新药开发有限公司 | Method for preparing high optical purity pitavastatin calcium raw material drug |
| WO2011105649A1 (en) * | 2010-02-24 | 2011-09-01 | (주)메디켐코리아 | New method for manufacturing pitavastatin hemicalcium using new intermediate |
| CN102653523A (en) * | 2011-12-17 | 2012-09-05 | 东莞达信生物技术有限公司 | Preparation method of pitavastatin calcium by recrystallization |
| CN102971297A (en) * | 2010-06-08 | 2013-03-13 | H.L.基因学 | Method for preparing an intermediate of pitavastatin or of the salt thereof |
| WO2013098773A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Crystalline forms of pitavastatin calcium |
| CN103848784A (en) * | 2012-12-05 | 2014-06-11 | 安徽省庆云医药化工有限公司 | Novel crystal form of pitavastatin and preparation method of novel crystal form |
| CN104072415A (en) * | 2014-05-16 | 2014-10-01 | 南通常佑药业科技有限公司 | Preparation method of pitavastatin calcium |
-
2017
- 2017-06-02 CN CN201710406204.9A patent/CN108976168B/en active Active
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1625550A (en) * | 2002-01-28 | 2005-06-08 | 诺瓦提斯公司 | Process for the manufacture of organic compounds |
| CN1876633A (en) * | 2005-06-10 | 2006-12-13 | 上海药明康德新药开发有限公司 | Method for preparing high optical purity pitavastatin calcium raw material drug |
| WO2011105649A1 (en) * | 2010-02-24 | 2011-09-01 | (주)메디켐코리아 | New method for manufacturing pitavastatin hemicalcium using new intermediate |
| CN102971297A (en) * | 2010-06-08 | 2013-03-13 | H.L.基因学 | Method for preparing an intermediate of pitavastatin or of the salt thereof |
| CN102653523A (en) * | 2011-12-17 | 2012-09-05 | 东莞达信生物技术有限公司 | Preparation method of pitavastatin calcium by recrystallization |
| WO2013098773A1 (en) * | 2011-12-28 | 2013-07-04 | Dr. Reddy's Laboratories Limited | Crystalline forms of pitavastatin calcium |
| CN103848784A (en) * | 2012-12-05 | 2014-06-11 | 安徽省庆云医药化工有限公司 | Novel crystal form of pitavastatin and preparation method of novel crystal form |
| CN104072415A (en) * | 2014-05-16 | 2014-10-01 | 南通常佑药业科技有限公司 | Preparation method of pitavastatin calcium |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109053568A (en) * | 2018-08-29 | 2018-12-21 | 南京卓康医药科技有限公司 | A kind of high-purity Pitavastatin Calcium novel crystal forms and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108976168B (en) | 2020-09-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107155326B (en) | Conformal adult salt and preparation method thereof | |
| AU2005256512B2 (en) | Crystalline forms of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol hydrochloride | |
| KR102078077B1 (en) | Crystalline form i of tyrosine kinase inhibitor dimaleate and preparation methods thereof | |
| EP0907639B1 (en) | Polymorphic compounds | |
| JP2017061536A (en) | Crystal form of quinoline compound and manufacturing method therefor | |
| EP2612855A1 (en) | Novel crystal of erlotinib base and the preparation method thereof | |
| CN1501910A (en) | Crystalline forms of venlafaxine hydrochloride | |
| CN108976168A (en) | A kind of half calcium salt novel crystal forms of Pitavastatin and preparation method thereof | |
| CN107033094A (en) | A kind of crystal formation of pharmaceutical co-crystals and preparation method thereof and composition | |
| RU2586117C2 (en) | Crystallisation of epirubicin hydrochloride | |
| US8686151B2 (en) | Montelukast 4-halobenzylamine salt and method for preparing montelukast sodium salt by using the same | |
| CN105315198A (en) | Crystal form of pirfenidone and preparation method of crystal form | |
| CN113549011B (en) | Dedostart eutectic or salt and preparation method and application thereof | |
| JP2010132561A (en) | New type a crystal of cibenzoline succinate and method for producing the same | |
| CN103130660B (en) | Acidic salt and crystal of dapoxetine and preparation method of crystal | |
| JP2021535218A (en) | New crystalline form of DPP-IV inhibitor hypoglycemic agent and its preparation method | |
| JP5952748B2 (en) | Novel crystalline form of phthaloyl amlodipine and process for producing high purity amlodipine besylate using the same | |
| WO2004096765A2 (en) | A novel crystalline polymorph of fluvastatin sodium and a process for preparing it | |
| CN101948426A (en) | New method for preparing aripiprazole crystal form B | |
| CA2610651A1 (en) | Process for preparing 3,3-diarylpropylamines | |
| CN102372672B (en) | Low-hygroscopicity aripiprazole crystal IV, its preparation method and application | |
| CN111217782A (en) | beraprost-314D monohydrate crystals and process for producing the same | |
| WO2006085338A2 (en) | Novel polymorphic forms of fluvastatin sodium and process for preparing the same | |
| CN110668990A (en) | Crystallization method for preparing high-purity monodisperse I crystal form atorvastatin calcium in single kettle | |
| CN113651802B (en) | One-pot preparation method of pitavastatin calcium intermediate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |