CN105017158B - A kind of preparation method of cis Rosuvastatin calcium impurities - Google Patents
A kind of preparation method of cis Rosuvastatin calcium impurities Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of cis Rosuvastatin calcium impurities; it is with (4R cis) 6 carboxaldehyde radicals 2; 2 dimethyl 1; the tert-butyl acetate of 3 dioxane 4 and [4 (4 fluorophenyl) 6 isopropyl 2 (N methyl N methylsulfonyls amido) 5 pyrimidine radicals] triphenylphosphinebromide are raw material; reacted through Witting, isomer separation, deprotection and hydrolysis, salt-forming reaction, be made target compound.The features such as this method has originality, simple to operate, convenient post-treatment, product purity height and high income.The beneficial effects of the invention are as follows：For rosuvastain calcium registration declare, produce in control and improve rosuvastain calcium quality certain help is provided.
Description
Technical field
The invention belongs to technical field of medicine synthesis, a kind of cis Rosuvastatin calcium impurities pair-[Z-7- is specifically related to
[4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) amino]-pyrimidine -5- bases] (3R, 5S) -3,5- dihydroxy
Hept- 6- olefin(e) acids] calcium salt (2:1) preparation method.
Background technology
Rosuvastain calcium, chemical name：Double-[E-7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- methane sulphurs
Amide groups) pyrimidine -5- bases]-(3R, 5S) -3,5- dihydroxy heptyls -6- (E)-olefin(e) acid] calcium salt (2:1), structure is as follows：
Rosuvastain calcium is a kind of cardiovascular drugs, is developed by Astrazeneca AB, and in November, 2002 head
First in Holland's approval listing.In August, 2003 obtains U.S. FDA approval, has completed to face in China in more than 60 country's listings at present
Bed experiment, trade name Crestor.The medicine has strong HMG-COA reductase actives, and it reduces LDL-C, rise
HDL-C effect, better than the other statinses listed, tolerance is good with security, is described as " superstatin ".2012
Year, Astrazeneca AB of Britain Crestor sales volume is to reach 62.53 hundred million dollars, with boundless market prospects.
Compound pair-[E-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) amino]-pyrimidine -5-
Base] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids] calcium salt (2:1) in preparation process, the compound (V) of E is wherein heavy
The reaction intermediate wanted, because witig reaction has the ratio of cis-trans-isomer, therefore is operated even across recrystallization etc.,
Still there is the residual of the compound (IV) of Z configurations in the compound (V) of E, therefore inevitably subsequent reactions form suitable
Formula Rosuvastatin calcium impurities, and there is influence to drug effect of medicine etc. in this impurity.
Therefore, for compound pair-[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) ammonia
Base]-pyrimidine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids] calcium salt (2:1) Research Significance is very big, and it can be used for
Controlled in the production of rosuvastain calcium, the qualitative and quantitative analysis of impurity, energy effective monitoring is simultaneously dropped using necessary means in time
Low impurity content, so as to improve the quality standard of rosuvastain calcium, it can also be used to which the registration of rosuvastain calcium is declared.
So far, only one document [Jan Fabris, Damjan Makuc, Zdenko Casar, Janez
Plavec.Conformational analysis of E/Z-isomeric pairs of rosuvastatin and its
Lactonized analogues, Tetrahedron, 69 (2013), 6262-6268] on compound pair-[Z-7- [4- (4-
Fluorine-based phenyl) -6- isopropyls -2- [methyl (mesyl) amino]-pyrimidine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- alkene
Acid] calcium salt (2:1) report of preparation method.The method of this document report is, it is necessary to using column chromatography, and cis-product is very difficult
To obtain (5% or so, obtained by column chromatography for separation).
The content of the invention
It is an object of the invention to make up the deficiencies in the prior art there is provided the compound that a kind of quality is good, purity is high it is double-
[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) amino]-pyrimidine -5- bases] (3R, 5S) -3,5- two
Hydroxyl hept- 6- olefin(e) acids] calcium salt (2:1) preparation method.
A kind of preparation method of cis Rosuvastatin calcium impurities, comprises the following steps：
(1) compound (II) (4R-cis) -6- carboxaldehyde radicals -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates and
Compound (III) [4- (4- fluorophenyls) -6- isopropyls -2- (N- methyl-N-methanesulfonamides base) -5- pyrimidine radicals] triphenyl phosphonium bromide
Witig reaction generation compound (IV) 6- [1Z-2]-[4- (4- fluorophenyls) -6- isopropyls -2- occurs in the presence of alkali for phosphine
[methyl (methylsulfonyl) amino] -5- pyrimidines] vinyl] -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates and chemical combination
Thing (V) 6- [1E-2]-[4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5- pyrimidines] vinyl] -2,2-
Dimethyl -1,3- dioxane -4- tert-butyl acetates；
(2) compound (IV) 6- [1Z-2]-[4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5-
Pyrimidine] vinyl] -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates catalytic amount acid in the presence of generate compound
(VI) (6Z) -7- [4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methanesulfonamido) pyrimidine -5- bases]-(3R, 5S) -3,5-
Dihydroxy heptyl -6- enoic acid ter-butyl esters；
(3) compound (VI) (6Z) -7- [4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methanesulfonamido) pyrimidine -5-
Base] reaction is hydrolyzed in-(3R, 5S) -3,5- dihydroxy heptyl -6- enoic acid ter-butyl esters and highly basic, and it is anti-then to carry out into salt with calcium salt
Cis rosuvastain calcium (I), chemical name should be formed:Double-[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (first
Sulfonyl) amino]-pyrimidine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids] calcium salt (2:1).
Course of reaction is as shown in Figure 3.
In step (1)：The alkali may be selected to common are machine alkali and inorganic base as acid binding agent, preferably, the alkali
One or more in potassium carbonate, sodium carbonate, triethylamine, sodium methoxide etc..
In step (1)：Described compound (III) [4- (4- fluorophenyls) -6- isopropyls -2- (N- methyl-N-methanesulfonamides
Base) -5- pyrimidine radicals] triphenylphosphinebromide, compound (II) (4R-cis) -6- carboxaldehyde radicals -2,2- dimethyl -1,3- dioxies six
The mol ratio of ring -4- tert-butyl acetates and alkali is 1：1~2：2~5；Further preferred mol ratio is 1：1~1.2：2~3.
In step (1)：Reaction dissolvent is selected from dimethyl sulfoxide (DMSO) (DMSO), acetone, DMF, N, N- diformazans
One or more in yl acetamide；The reaction dissolvent is more preferably dimethyl sulfoxide (DMSO).
In step (1)：The reaction temperature of the witig reaction is 60~100 DEG C；Further preferred reaction temperature is
70~80 DEG C；It is preferred that reaction time be 1~8 hour, more preferably 2~4 hours.
In step (1)：After reaction terminates, by post processing can respectively obtain compound (IV) 6- [1Z-2] of high-purity-
[4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5- pyrimidines] vinyl] -2,2- dimethyl -1,3- two
Ring -4- the tert-butyl acetates of oxygen six and compound (V) 6- [1E-2]-[4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl)
Amino] -5- pyrimidines] vinyl] -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates.Wherein compound (IV) 6-
[1Z-2]-[4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5- pyrimidines] vinyl] -2,2- dimethyl -
1,3- dioxane -4- tert-butyl acetates are used as the raw material of step (2)；Compound (V) 6- [1E-2]-[4- (4- fluorobenzene
Base) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5- pyrimidines] vinyl] -2,2- dimethyl -1,3- dioxane -4- second
Tert-butyl acrylate can be used as the raw material for preparing trans rosuvastain calcium.
Above-mentioned post-processing approach is preferably：
(1) after reaction terminates, using toluene extraction system liquid, organic solvent is removed, the recrystallization solvent weight such as methanol is utilized
Crystallization obtain E (trans) product 6- [1E-2]-[4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -
5- pyrimidines] vinyl] -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates；
(2) mother liquor being recrystallized to give removes solvent, adds hexamethylene, is heated to dissolving, and cooling removes the solid separated out
(mainly triphenylphosphine oxide), then removes solvent, Z configurations (cis) product 6- [1Z- is recrystallized to give using recrystallization solvent
2]-[4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5- pyrimidines] vinyl] -2,2- dimethyl -1,3-
Dioxane -4- tert-butyl acetates.Preferably, mother liquor remove triphenylphosphine oxide after recrystallization solvent for use be methanol, ethanol,
Isopropanol.
In step (2)：The acid can typically use hydrochloric acid, and addition is catalytic amount, for example, can be reaction substrate compound
(IV) the 5~10% of integral molar quantity.
In step (2)：Acetonitrile may be selected in reaction dissolvent；Reaction temperature is generally 40~70 DEG C, more preferably 50~
55℃；Reaction time is generally 1~3 hour, more preferably 2~2.5 hours；
, can not be post-treated after the completion of step (2) reaction, directly carry out step (3)；The highly basic is generally sodium hydroxide
Or potassium hydroxide；The amount that highly basic is added, so that the pH value for the system of obtaining is 10~14.After reaction completely, using acid by system
Faintly acid is arrived in pH value regulation, then can obtain Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyl -2- [first using organic molten extraction
Base (mesyl) amino]-pyrimidine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids, the extractant of use is generally second
Merge organic phase after acetoacetic ester, extraction.Calcium saline solution, Z-7- [4- (the fluorine-based benzene of 4- are directly added into the organic phase of merging
Base) -6- isopropyls -2- [methyl (mesyl) amino]-pyrimidine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids and calcium
Salt is that can obtain final product pair-[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) ammonia into salt
Base]-pyrimidine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids] calcium salt (2:1), final product is dissolved in organic phase, is gone
Except organic phase is that can obtain product of the invention.Described calcium salt is preferably calcium chloride.
The present invention is with the tertiary fourth of dimethyl -1,3- dioxane -4- acetic acid of compound (II) (4R-cis) -6- carboxaldehyde radicals -2,2
Ester and compound (III) [4- (4- fluorophenyls) -6- isopropyls -2- (N- methyl-N-methanesulfonamides base) -5- pyrimidine radicals] triphenyl
Bromide phosphine is raw material, is reacted through Witting, separates Witting reactions cis-isomer, deprotection and hydrolysis salifying reaction, system
Target compound is obtained, and through 1H-NMR, 13C-NMR, HSQC, HMBC and DEPT-135, mass spectroscopy structural confirms.
The preparation method of the present invention has the spies such as originality, simple to operate, convenient post-treatment, product purity height and yield height
Point.The beneficial effects of the invention are as follows：For rosuvastain calcium registration declare, produce in control and improve rosuvastain calcium
Quality provides certain help.
Brief description of the drawings
Fig. 1 is the HPLC figures for the E compound (V) that embodiment 1 is prepared；
Fig. 2 is the HPLC figures for the Z configuration of compound (IV) that embodiment 1 is prepared；
Fig. 3 is the course of reaction figure of the preparation method of the cis Rosuvastatin calcium impurities of the present invention.
Embodiment
The present invention is further described by the following examples, but these embodiments are merely illustrative, not to this hair
Bright protection domain constitutes any limitation, it will be apparent to a skilled person that the replacement done according to spirit of the invention,
Modification each falls within protection scope of the present invention.
Embodiment 1：
The compounds of this invention pair-[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) amino] -
Pyrimidine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids] calcium salt (2:1) preparation method, using following steps：
(1) compound (IV) 6- [(1Z) -2- [4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5-
Pyrimidine] vinyl] -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates and compound (V) 6- [(1E) -2- [4- (4-
Fluorophenyl) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5- pyrimidines] vinyl] -2,2- dimethyl -1,3- dioxane -
The preparation of 4- tert-butyl acetates：
DMSO 250ml and 19g D7 ((4R-cis) -6- carboxaldehyde radicals -2,2- diformazans are added into 1000mL four-hole boiling flasks
Base -1,3- dioxane -4- tert-butyl acetates), add Z8.2 ([4- (4- fluorophenyls) -6- isopropyls -2- (N- methyl-N- first
Sulfoamido) -5- pyrimidine radicals] triphenylphosphinebromide) 45g, add potassium carbonate 20.8g, heating, 75 DEG C of insulation 2h, Z8.2 reactions
After completely, 20 DEG C are cooled to, toluene 200ml is added, agitation and filtration, organic layer adds 200ml water, stirs 10min.Divide liquid, water
Layer is extracted with 100ml toluene, merges organic phase, with 200ml*2 water washings twice, and organic layer is decompressed to dry, and recrystallizing methanol obtains E
Configuration (trans) product, HPLC purity 99% (see accompanying drawing 1).Mother liquor adds 500ml hexamethylenes after being spin-dried for, and is warming up to dissolved clarification, drops
Temperature, has solid to separate out (triphenylphosphine oxide), is cooled to 10 DEG C, is incubated 2h, and suction filtration is eluted with 50ml hexamethylenes.Mother liquor is in 45 DEG C
Dry, addition 300ml methanol is decompressed to, dissolving, decompression is threaded to about surplus 100ml, and stirring, slow cooling has solid precipitation, is cooled to
10 DEG C, 2h is incubated, suction filtration is eluted with 20ml methanol, 50 DEG C of drying of filter cake, (HPLC spectrograms are shown in attached to Z configurations (cis) purity 97%
Fig. 1,1H-NMR spectrum is shown in accompanying drawing 2).
E nuclear-magnetism characterize data：1H-NMR, CDCl3,400MHz,δ7.63[dd,2H],7.07[t,2H],6.52[dd,
1H, J=16.0Hz], 5.47 [dd, 1H, J=16.4Hz], 4.41 [m, 1H], 4.26 [m, 1H], 3.55 [s, 3H], 3.50 [s,
3H],3.36[m,1H],2.26-2.44[2×dd,2H],1.55-1.08[m,2H,],1.52[s,3H],1.44[s,3H],
1.45[s,9H],1.27[dd,6H]。
Z configuration nuclear-magnetism characterize datas：1H-NMR, CDCl3,400MHz,δ7.74[brs,2H],7.10[t,2H],6.53[d,
1H, J=8.8Hz], 5.61 [dd, 1H, J=11.2Hz], 4.01 [m, 2H], 3.60 [s, 3H], 3.53 [s, 3H], 3.30 [m,
1H],2.20[m,2H],1.40[s,9H],1.06-1.24[m,14H]。
(2) compound pair-[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) amino]-phonetic
Pyridine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids] calcium salt (2:1) preparation：
6- [(1Z) -2- [4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) is added in 250ml four-hole boiling flasks
Amino] -5- pyrimidines] vinyl] in -2,2- dimethyl-1,3-dioxanes -4- tert-butyl acetate 5g, acetonitrile 80ml, 30min
The hydrochloric acid of catalytic amount is dripped, 50 DEG C of insulation reactions are continued at 2 hours, it is rear to add 2N sodium hydroxide aqueous, pH is entered for 10-11
Row hydrolysis, is concentrated to dryness, plus 60ml purified waters after TLC display reactions completely, with 2N salt acid for adjusting pH value to 3, twice
20ml ethyl acetate is extracted, and merges organic phase, CaCl is added afterwards2Solution, stirring reaction, layering, organic phase is spin-dried for obtaining class white
Color solid pair-[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) amino]-pyrimidine -5- bases] (3R,
5S) -3,5- dihydroxy heptyls -6- olefin(e) acids] calcium salt (2:1) 3.5g, yield 80.8%, nuclear-magnetism characterize data is consistent with document.
Embodiment 2：
The compounds of this invention pair-[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) amino] -
Pyrimidine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids] calcium salt (2:1) preparation method, using following steps：
(1) compound (IV) 6- [(1Z) -2- [4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5-
Pyrimidine] vinyl] -2,2- dimethyl -1,3- dioxane -4- tert-butyl acetates and compound (V) 6- [(1E) -2- [4- (4-
Fluorophenyl) -6- isopropyls -2- [methyl (methylsulfonyl) amino] -5- pyrimidines] vinyl] -2,2- dimethyl -1,3- dioxane -
The preparation of 4- tert-butyl acetates：
DMF 250ml and 20g D7 are added into 1000mL four-hole boiling flasks, Z8.245g is added, potassium carbonate 20.8g is added,
Heating, after 80 DEG C of insulation 2h, Z8.2 reactions completely, is cooled to 20 DEG C, adds toluene 200ml, agitation and filtration, organic layer is added
200ml water, stirs 10min.Divide liquid, water layer is extracted with 100ml toluene, merges organic phase, with 200ml*2 water washings twice, has
Machine layer is decompressed to dry, and recrystallizing methanol obtains E (trans) product, HPLC purity 99%.Mother liquor adds 500ml hexamethylenes after being spin-dried for
Alkane, is warming up to dissolved clarification, cooling, has solid to separate out (triphenylphosphine oxide), is cooled to 10 DEG C, is incubated 2h, and suction filtration uses 50ml hexamethylenes
Elution.Mother liquor is decompressed to dry, addition 300ml methanol in 45 DEG C, and dissolving, decompression is threaded to about surplus 100ml, and stirring, slow cooling has
Solid is separated out, and is cooled to 10 DEG C, is incubated 2h, and suction filtration is eluted with 20ml methanol, 50 DEG C of drying of filter cake, Z configurations (cis) purity
96.5%.
(2) compound pair-[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) amino]-phonetic
Pyridine -5- bases] (3R, 5S) -3,5- dihydroxy heptyl -6- olefin(e) acids] calcium salt (2:1) preparation：
6- [(1Z) -2- [4- (4- fluorophenyls) -6- isopropyls -2- [methyl (methylsulfonyl) is added in 250ml four-hole boiling flasks
Amino] -5- pyrimidines] vinyl] in -2,2- dimethyl-1,3-dioxanes -4- tert-butyl acetate 5g, acetonitrile 80ml, 30min
The hydrochloric acid of catalytic amount is dripped, 50 DEG C of insulation reactions are continued at 2 hours, it is rear to add 2N sodium hydroxide aqueous, pH is entered for 11-12
Row hydrolysis, is concentrated to dryness, plus 60ml purified waters after TLC display reactions completely, with 2N salt acid for adjusting pH value to 3, twice
20ml ethyl acetate is extracted, and merges organic phase, CaCl is added afterwards2Solution, stirring reaction, layering, organic phase is spin-dried for obtaining class white
Color solid pair-[Z-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl) amino]-pyrimidine -5- bases] (3R,
5S) -3,5- dihydroxy heptyls -6- olefin(e) acids] calcium salt (2:1) 3.3g, yield 79.2%, nuclear-magnetism characterize data is consistent with document.
Claims (9)
1. a kind of preparation method of cis Rosuvastatin calcium impurities, it is characterised in that comprise the following steps：
(1) witig reaction generation compound (IV) and chemical combination occur in the presence of alkali for compound (II) and compound (III)
Thing (V)；
The structure difference of compound (II)~(V) is as follows：
After step (1) reaction terminates, post-processing approach is：
(1-1) utilizes toluene extraction system liquid, obtains the mixture containing compound (IV), compound (V) and triphenylphosphine oxide,
Compound (V) is recrystallized to give using recrystallization solvent；
The mother liquor that (1-2) is recrystallized to give removes solvent, adds hexamethylene, is heated to dissolving, and cooling removes the solid separated out,
Solvent is removed, compound (IV) is recrystallized to give using recrystallization solvent；
The recrystallization solvent is the one or more in methanol, ethanol, isopropanol；
(2) compound (IV) is deprotected generation compound (VI) under the action of an acid, and the structure of compound (VI) is as follows：
(3) reaction is hydrolyzed with highly basic in compound (VI), and then carrying out salt-forming reaction with calcium salt forms cis Rosuvastatin
Calcium, structure is as follows：
2. the preparation method of cis Rosuvastatin calcium impurities according to claim 1, it is characterised in that in step (1)：
One or more of the alkali in potassium carbonate, sodium carbonate, triethylamine, sodium methoxide.
3. the preparation method of cis Rosuvastatin calcium impurities according to claim 1, it is characterised in that the compound
(III), compound (II) and the mol ratio of alkali are 1：1~2：2~5.
4. the preparation method of cis Rosuvastatin calcium impurities according to claim 1, it is characterised in that in step (1)：
One or more of the reaction dissolvent in dimethyl sulfoxide (DMSO), acetone, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide.
5. the preparation method of cis Rosuvastatin calcium impurities according to claim 1, it is characterised in that the Wei Tixi
The reaction temperature of reaction is 60~100 DEG C.
6. the preparation method of cis Rosuvastatin calcium impurities according to claim 1, it is characterised in that in step (2)：
The acid is hydrochloric acid, and addition is catalytic amount.
7. the preparation method of cis Rosuvastatin calcium impurities according to claim 1, it is characterised in that in step (2)：
Reaction dissolvent is acetonitrile.
8. the preparation method of cis Rosuvastatin calcium impurities according to claim 1, it is characterised in that in step (2)：
Reaction temperature is 40~70 DEG C.
9. the preparation method of cis Rosuvastatin calcium impurities according to claim 1, it is characterised in that step (2) is anti-
After the completion of answering, without post processing, step (3) is directly carried out；In step (3), add highly basic and cause the pH value of system to be 10~14.
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| CN1307187C (en) * | 2005-05-16 | 2007-03-28 | 浙江海正药业股份有限公司 | Method for preparing Rosuvastain and its intermediate |
| SI2665722T1 (en) * | 2011-01-18 | 2016-12-30 | Dsm Sinochem Pharmaceuticals Netherlands B.V. | Process for the preparation of diol sulfones |
| CN103776939A (en) * | 2014-02-11 | 2014-05-07 | 润泽制药(苏州)有限公司 | Preparation detection method for substances related to rosuvastatin calcium preparation |
| CN103936680B (en) * | 2014-04-18 | 2016-08-24 | 润泽制药(苏州)有限公司 | The preparation method of rosuvastain calcium known impurities |
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