CN104844525B - A kind of preparation method of Rosuvastatin calcium impurities - Google Patents
A kind of preparation method of Rosuvastatin calcium impurities Download PDFInfo
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Abstract
The invention discloses a kind of preparation method of Rosuvastatin calcium impurities; it is using the base of 4 (4 fluorophenyl) 6 isopropyl 2 (N methyl N sulfonyl methanes amido) pyrimidine 5] formaldehyde and (3R) 3 tertiary butyl dimethyl Si base 5 carbonyl 6 (triphen phosphino- vinyl) methyl caproate is raw material; reacted through Witting, HF deprotections, alkaline hydrolysis and acidification reaction, target compound is made.The features such as this method has short, simple to operate synthetic route, 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 present invention relates to a kind of compound 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido)
Pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid preparation method, belong to technical field of medicine synthesis.
Background technology
Rosuvastain calcium, chemical name：Double-[7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes
Amido) pyrimidine -5- bases]-(3R, 5S) -3,5- dihydroxy heptyls -6- (E)-olefin(e) acid] calcium salt (2:1).It is a kind of cardiovascular drugs,
Developed by Astrazeneca AB, and in November, 2002 first in Holland's approval listing.In August, 2003 obtains U.S. FDA batch
Standard, has completed clinical test, trade name Crestor in more than 60 country's listings in China at present.The medicine has strong
HMG-COA reductase actives, its reduce LDL-C, raise HDL-C effect, better than the other statins listed
Thing, tolerance is good with security, is described as " superstatin ".2012, Astrazeneca AB of Britain Crestor sales volume was
62.53 hundred million dollars are reached, with boundless market prospects.
Compound 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases] -
(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid (CAS：1422619-13-3) result from the preparation process of rosuvastain calcium
In, its with calcium salt reaction generation it is double-[7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -
5- yls]-(3R)-hydroxyl -5- carbonyl hept- 6- (E)-olefin(e) acid] calcium salt (2:1), as the relevant substance C of rosuvastain calcium (EP mark
Standard, RRT=1.50).Therefore, for compound 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- Methanesulfonamides
Base) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid Research Significance it is very big, its can be used for Rosuvastain
Controlled in the production of spit of fland calcium, the qualitative and quantitative analysis of impurity, energy effective monitoring is simultaneously contained using necessary means reduction impurity in time
Amount, so as to improve the quality standard of rosuvastain calcium, it can also be used to which the registration of rosuvastain calcium is declared.
Application publication number discloses following reaction for CN 103936680A patent document：
Its purpose product prepared is double-[E-7- [4- (the fluorine-based phenyl of 4-) -6- isopropyls -2- [methyl (mesyl)
Amino]-pyrimidine -5- bases] -3R-3- hydroxyl -5- oxo -6- heptenoic acids] calcium salt), the applicant once attempted directly to use compound
(+)-(3R) -7- [4- (4- fluorophenyls) -6- isopropyls -2- [N- methyl-N- (methylsulfonyl) amino]-pyrimidine -5- bases] -3- hydroxyls
Base -5- oxos-(6E)-heptene tert-butyl acrylate prepares 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- first as substrate
Alkyl sulfonamide base) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid, but found in experimentation, the substrate
It can not buy from the market, it is necessary to be prepared according to document report synthesis technique, but the synthesis technique of document report is very
Complexity, including complicated and course of reaction are difficult to the oxidation reaction of control, relatively low (the only manganese oxide oxidation step yield of the substrate yield
Only 70%), it greatly limit overall yield.
So far, it is not yet found that researcher is on compound 7- [4- (4- fluorophenyls) (N- first of -6- isopropyls -2
Base-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid preparation method report.
The content of the invention
It is an object of the invention to make up the deficiencies in the prior art, there is provided a kind of quality is good, purity is high, high income chemical combination
Thing 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls
Base -6- (E)-heptenoic acid preparation method.
The purpose of the present invention is achieved by the following technical solution：
A kind of preparation method of Rosuvastatin calcium impurities, including：
(1) by 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases] -
(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid methyl esters (H2) carries out Basic fluxing raction with alkali, obtains compound 7- [4- (4- fluorobenzene
Base) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid
Salt；
(2) 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R) -
Hydroxyl -5- carbonyls -6- (E)-heptene hydrochlorate carries out acidification reaction with acid, and obtaining target compound 7-, [4- (4- fluorophenyls) -6- is different
Propyl group -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid (I).
7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl
The structure of base -5- carbonyls -6- (E)-heptenoic acid (I) is as follows：
From 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R) -
Hydroxyl -5- carbonyls -6- (E)-heptenoic acid methyl esters (H2) is raw material, be the advantage is that, the compound is to prepare Rosuvastain in itself
The intermediate of spit of fland calcium, you can buy from the market, while can be prepared using existing method, preferably, can be using such as
Lower section method is prepared, including：
A, 4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-formaldehyde (Z9) and
(3R) -3- tertiary butyl dimethyl Si base -5- carbonyls -6- (triphen phosphino- vinyl)-methyl caproate (J6) reacts through Witting
Prepare 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R) -3- uncles
Butyldimethylsilanyloxy -5- carbonyls -6- (E)-heptenoic acid methyl esters (H1)；
B, 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R) -3-
Tertiary butyl dimethyl Si base -5- carbonyls -6- (E)-heptenoic acid methyl esters (H1) and aqueous hydrogen fluoride solution reaction generation 7- [4- (4-
Fluorophenyl) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptan
E pioic acid methyl ester (H2)；
When being prepared using the above method, 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido)
Pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid methyl esters (H2) preparation technology is simple, and high income, total recovery can
More than 80%, and in documents, compound (+)-(3R) -7- [4- (4- fluorophenyls) -6- isopropyls -2- [N- methyl-N-
(methylsulfonyl) amino]-pyrimidine -5- bases] -3- hydroxyl -5- oxos-(6E)-heptene tert-butyl acrylate yield only below 70%.
The present invention synthetic route be：
Preferably, in step a, 4- (4- the fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) are phonetic
Pyridine -5- bases]-formaldehyde (Z9) and (3R) -3- tertiary butyl dimethyl Si base -5- carbonyls -6- (triphen phosphino- vinyl)-caproic acid first
The mol ratio of ester (J6) is generally 1:1-2, more preferably 1：1-1.2.
Preferably, in step a, reaction dissolvent can react conventional solvent using Witting, such as can use acetonitrile
Deng.In the step, reaction temperature is generally 50-100 DEG C.
After step a reactions terminate, following last handling process can be used：Be concentrated under reduced pressure removal reaction dissolvent, adds hexamethylene
It is one or many, hexamethylene is evaporated again after adding hexamethylene every time, further to remove reaction dissolvent, hexamethylene is eventually adding
Some, back flow reaction 0.5-2h is cooled to 10~15 DEG C of insulation 1.5-2.5h, and filtering, filtrate decompression is concentrated to dryness, is directly used in
Next step is reacted.
In step b, reaction dissolvent can also use acetonitrile, and the mole of the hydrofluoric acid of addition is different for 4- (4- fluorophenyls) -6-
Propyl group -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases] 8-20 times, more preferably 10-15 times of-formaldehyde (Z9).
Further, in the preparation method step (1) of the compound, solvent for use be methanol, ethanol, isopropanol,
Acetonitrile, acetone, toluene, benzene, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, dimethylacetylamide, chloroform, dichloromethane,
Ethylene glycol, glycerine, N-METHYLFORMAMIDE, N- ethyl acetamides, sulfolane, 1-METHYLPYRROLIDONE, 2- nitroethyl alcohols, 2- fluorine second
Alcohol, 2,2,2 tfifluoroethyl alcohol, 1- propyl alcohol, 2- methoxypropanols, n-butyl alcohol, isobutanol, the tert-butyl alcohol, cellosolvo, diethyl
Glycol, 1- amylalcohols, 2- amylalcohols, 3- amylalcohols, 2,2- dimethyl -1- propyl alcohol, cyclohexanol, methyl phenyl ethers anisole, phenmethylol, ether, methyl- tert
Butyl ether, diethylene glycol monomethyl ether, chlorobenzene, butoxy ethanol, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol
One or more in diethyl ether, TRIGLYME, tetrahydrofuran, ethyl acetate, methyl acetate and water, preferably tetrahydrochysene furan
Mutter and one kind in water mixed solvent, acetonitrile, methanol and water mixed solvent；Alkali used can be various inorganic bases or organic base,
It is preferred that one kind in hydroxide, caustic alcohol, n-BuLi, sodium methoxide, carbonate, pyridine, triethylamine；The temperature of Basic fluxing raction
For -20~40 DEG C, preferably 0~25 DEG C.
In step (1), addition 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -
5- yls] mol ratio of-(3R) -3- hydroxyl -5- carbonyls -6- (E)-heptenoic acid methyl esters and alkali is generally 1:1-5, more preferably
1:1.1-1.5.It is added dropwise during alkali, generally requiring control system temperature can not be too high, preferably, when adding alkali, control volume
It is that temperature is 10~15 DEG C.
Yet further, in the preparation method step (2) of the compound, solvent for use be methanol, ethanol, isopropanol,
Acetonitrile, acetone, toluene, benzene, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, dimethylacetylamide, chloroform, dichloromethane,
Ethylene glycol, glycerine, N-METHYLFORMAMIDE, N- ethyl acetamides, sulfolane, 1-METHYLPYRROLIDONE, 2- nitroethyl alcohols, 2- fluorine second
Alcohol, 2,2,2 tfifluoroethyl alcohol, 1- propyl alcohol, 2- methoxypropanols, n-butyl alcohol, isobutanol, the tert-butyl alcohol, cellosolvo, diethyl
Glycol, 1- amylalcohols, 2- amylalcohols, 3- amylalcohols, 2,2- dimethyl -1- propyl alcohol, cyclohexanol, methyl phenyl ethers anisole, phenmethylol, ether, methyl- tert
Butyl ether, diethylene glycol monomethyl ether, chlorobenzene, butoxy ethanol, diethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol
One or more in diethyl ether, TRIGLYME, tetrahydrofuran, ethyl acetate, methyl acetate and water, preferably tetrahydrochysene furan
Mutter, one in ethyl acetate, methyl acetate, acetonitrile, ether, methyl tertiary butyl ether(MTBE), toluene, dichloromethane, chloroform and water
Plant or several；Acid used is the one or more in hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid；Reaction temperature -20~40
DEG C, preferably 5~20 DEG C；PH is controlled after acidifying<7, preferably pH are 2~5；The reaction time is controlled to be less than 24h, preferably 5~20min.
The present invention is with 4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-formaldehyde
(3R) -3- tertiary butyl dimethyl Si base -5- carbonyls -6- (triphen phosphino- vinyl)-methyl caproate is raw material, warp
Witting reactions, HF deprotections, alkaline hydrolysis and acidification reaction, are made target compound, and pass through1H-NMR、13C-NMR、HSQC、
HMBC and DEPT-135 structural confirmations.
Alkaline hydrolysis and acidifying total recovery bring up to 96.1% in the present invention.Using 4- (4- fluorophenyls) (the N- first of -6- isopropyls -2
Base-N- sulfonyl methanes amido) pyrimidine -5- bases]-formaldehyde be raw material when, overall yield is maintained at more than 84%.
Abandoning tradition prejudice of the present invention, selection source is easy to get, while preparing simple compound for raw material, this method has
Synthetic route is short, simple to operate, convenient post-treatment, product purity are high and the features such as high income.The beneficial effects of the invention are as follows：For
The registration of rosuvastain calcium declares, produce in control and improve the quality of rosuvastain calcium certain help be provided.
Brief description of the drawings
7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- Methanesulfonamides that Fig. 1 prepares for the present invention
Base) pyrimidine -5- bases]-(3R) -3- hydroxyl -5- carbonyls -6- (E)-heptenoic acid HPLC figure.
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 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5-
Base]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid preparation method, using following steps：
A, compound 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases] -
The preparation of (3R) -3- tertiary butyl dimethyl Si base -5- carbonyls -6- (E)-heptenoic acid methyl esters (H1)：
4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) are added in 500ml four-hole boiling flasks phonetic
Pyridine -5- bases]-formaldehyde (Z9,10g, 28.5mmol), (3R) -3- tertiary butyl dimethyl Si base -5- carbonyls -6- (triphen phosphino- second
Alkenyl)-methyl caproate (J6,16.76g, 31.3mmol) and acetonitrile 250ml, mechanical agitation, back flow reaction about 30h, HPLC prison
Control, after question response is complete, is concentrated under reduced pressure into dry, it is dry twice to be separately added into hexamethylene 60ml revolving bands, adds hexamethylene
200ml, back flow reaction 1h, are cooled to 10~15 DEG C of insulation 2h, and filtering, filtrate decompression is concentrated to dryness, and is directly used in next step anti-
Should.
B, compound 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases] -
The preparation of (3R) -3- hydroxyl -5- carbonyls -6- (E)-heptenoic acid methyl esters (H2)：
Above-mentioned concentrate and acetonitrile 150ml are added in 500ml four-hole boiling flasks, 0~5 DEG C is cooled to, 49%HF is added dropwise
(11.63g, 285mmol) and acetonitrile 150ml mixed solutions, drop is warmed to room temperature after finishing, stirring reaction 6h, adds sodium bicarbonate water
Solution neutralization reaction, stratification, aqueous phase is extracted twice with methyl tertiary butyl ether(MTBE), merges organic phase, saturated aqueous common salt and distillation
Water washing twice, dried by anhydrous magnesium sulfate, and filtering, filtrate decompression is spin-dried for, ethyl acetate and petroleum ether mixed solvent recrystallization, is obtained
To faint yellow solid 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R) -
3- hydroxyl -5- carbonyls -6- (E)-heptenoic acid methyl esters 15.17g, two step yields 87.6%, HPLC detection purity 97.9%.
C, compound 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases] -
The preparation of (3R) -3- hydroxyl -5- carbonyls -6- (E)-heptenoic acid sodium：
7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- Methanesulfonamides are added in 500ml four-hole boiling flasks
Base) pyrimidine -5- bases]-(3R) -3- hydroxyl -5- carbonyls -6- (E)-heptenoic acid methyl esters (H2,5.0g, 10.1mmol), tetrahydrofuran
80ml and water 80ml, under the conditions of 10~15 DEG C, is slowly added dropwise 0.25mol/L NaOH solution 50ml, drop finishes, stirring reaction
30min.After reaction terminates, it is concentrated under reduced pressure, organic solvent is evaporated off, aqueous phase is extracted 3 times with methyl tertiary butyl ether(MTBE), and aqueous phase is no longer pure
Change, be directly used in next step.
D, compound 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases] -
The preparation of (3R) -3- hydroxyl -5- carbonyls -6- (E)-heptenoic acid (I)：
Above-mentioned aqueous phase, methyl tertiary butyl ether(MTBE) 50ml and water 30ml are added in 250ml four-hole boiling flasks, in 5~10 DEG C of conditions
Under, 2M HCl are slowly added dropwise, adjust to pH=3~4, stirring reaction 15min, stratification, aqueous phase is extracted with methyl tertiary butyl ether(MTBE)
Take twice, merge organic phase, organic phase is washed twice respectively with saturated aqueous common salt and water, anhydrous magnesium sulfate is dried, filtering, filtrate
Dry (temperature is less than 20 DEG C) is decompressed to, off-white powder 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- methane is obtained
Sulfoamido) pyrimidine -5- bases]-(3R) -3- hydroxyl -5- carbonyls -6- (E)-heptenoic acid 4.67g, two step yields 96.1%, HPLC
Detect purity 98.3% (see accompanying drawing 1).
Nuclear-magnetism characterize data：1H-NMR, CDCl3, 400MHz, 7.64 (d, J=16.4Hz, 1H), 7.58 (dd, J=
8.8Hz, 5.2Hz, 2H), 7.14 (t, J=8.4Hz, 2H), 6.16 (d, J=16.4Hz, 1H), 4.47-4.53 (m, 1H), 3.57
(s, 3H), 3.51 (s, 3H), 3.32-3.38 (m, 1H), 2.74-2.77 (m, 2H), 2.56 (d, J=6.0Hz, 2H), 1.29 (s,
3H),1.28(s,3H)。
For step C, tetrahydrofuran is replaced with to acetonitrile, carbinol mixture (volume ratio 1 respectively:1) step D is constant, most
Two step yields are between 95-97% eventually.
Meanwhile, step C is constant, and for step D, methyl tertiary butyl ether(MTBE) is replaced with tetrahydrofuran, ethyl acetate, second by us
Sour methyl esters, acetonitrile, ether, methyl tertiary butyl ether(MTBE), toluene, dichloromethane, chloroform, final two steps yield 96-97% it
Between.
In step C, alkali can be replaced hydroxide, caustic alcohol, n-BuLi, sodium methoxide, carbonate, pyridine, triethylamine
In one kind, little is influenceed on ultimate yield.
In step D, one kind in acid optional hydrochloric acid, phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid, yield 94-96% it
Between.
Claims (7)
1. a kind of preparation method of Rosuvastatin calcium impurities, including：
(1) by 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl
Base -5- carbonyls -6- (E)-heptenoic acid methyl esters carries out Basic fluxing raction with alkali, obtains compound 7- [4- (4- fluorophenyls) -6- isopropyls
Base -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptene hydrochlorate；Reaction is molten
Agent is the mixed solvent of tetrahydrofuran and water, or acetonitrile, the mixed solvent of first alcohol and water；
(2) by 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl
Base -5- carbonyls -6- (E)-heptene hydrochlorate carries out acidification reaction with acid, obtains target compound 7- [4- (4- fluorophenyls) -6- isopropyls
Base -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid；
7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(the 3R)-hydroxyl
Base -5- carbonyls -6- (E)-heptenoic acid methyl esters structure is as follows：
7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(the 3R)-hydroxyl
The structure of base -5- carbonyls -6- (E)-heptenoic acid is as follows：
7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(the 3R)-hydroxyl
Base -5- carbonyls -6- (E)-heptenoic acid methyl esters is prepared by following methods：
A, 4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-formaldehyde and (3R) -3-
Tertiary butyl dimethyl Si base -5- carbonyls -6- (triphen phosphino- vinyl)-methyl caproates obtain 7- [4- through Witting reactions
(4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R) -3- tert-butyldimethyl silyls
Epoxide -5- carbonyls -6- (E)-heptenoic acid methyl esters；
After wherein step a reactions terminate, be concentrated under reduced pressure removal reaction dissolvent, and addition hexamethylene is one or many, and ring is added every time
Hexamethylene is evaporated again after hexane, further to remove reaction dissolvent, it is some to be eventually adding hexamethylene, back flow reaction 0.5-2h,
10~15 DEG C of insulation 1.5-2.5h are cooled to, filtering, filtrate decompression is concentrated to dryness, and is directly used in next step reaction；
B, 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-tertiary fourths of (3R) -3-
Base dimethylsilyl bis -5- carbonyls -6- (E)-heptenoic acid methyl esters and aqueous hydrogen fluoride solution reaction generation 7- [4- (4- fluorophenyls) -
6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R)-hydroxyl -5- carbonyls -6- (E)-heptenoic acid first
Ester；
4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-formaldehyde structure such as
Under：
The structure of (3R) -3- tertiary butyl dimethyl Sis base -5- carbonyls -6- (triphen phosphino- the vinyl)-methyl caproate is such as
Under：
Described 7- [4- (4- fluorophenyls) -6- isopropyls -2 (N- methyl-N- sulfonyl methanes amido) pyrimidine -5- bases]-(3R) -3- uncles
The structure of Butyldimethylsilanyloxy -5- carbonyls -6- (E)-heptenoic acid methyl esters is as follows：
2. the preparation method of Rosuvastatin calcium impurities according to claim 1, it is characterised in that alkali used is hydroxide
One or more in thing, caustic alcohol, n-BuLi, sodium methoxide, carbonate, pyridine, triethylamine.
3. the preparation method of Rosuvastatin calcium impurities according to claim 1, it is characterised in that the Basic fluxing raction
Temperature is -20~40 DEG C.
4. the preparation method of Rosuvastatin calcium impurities according to claim 1, it is characterised in that molten used by acidification reaction
Agent is methanol, ethanol, isopropanol, acetonitrile, acetone, toluene, benzene, dimethyl sulfoxide (DMSO), N,N-dimethylformamide, dimethylacetamide
Amine, chloroform, dichloromethane, ethylene glycol, glycerine, N-METHYLFORMAMIDE, N- ethyl acetamides, sulfolane, N- methylpyrroles
Alkanone, 2- nitroethyl alcohols, 2- fluoroethanols, 2,2,2 tfifluoroethyl alcohol, 1- propyl alcohol, 2- methoxypropanols, n-butyl alcohol, isobutanol, uncle
Butanol, cellosolvo, diethylene glycol, 1- amylalcohols, 2- amylalcohols, 3- amylalcohols, 2,2- dimethyl -1- propyl alcohol, cyclohexanol, benzene first
Ether, phenmethylol, ether, methyl tertiary butyl ether(MTBE), diethylene glycol monomethyl ether, chlorobenzene, butoxy ethanol, diethylene glycol dimethyl ether, two
In glycol dimethyl ether, diethylene glycol diethyl ether, TRIGLYME, tetrahydrofuran, ethyl acetate, methyl acetate and water
It is one or more of.
5. the preparation method of Rosuvastatin calcium impurities according to claim 4, it is characterised in that molten used by acidification reaction
Agent is tetrahydrofuran, ethyl acetate, methyl acetate, acetonitrile, ether, methyl tertiary butyl ether(MTBE), toluene, dichloromethane, chloroform
With the one or more in water.
6. the preparation method of Rosuvastatin calcium impurities according to claim 4, it is characterised in that acid used is hydrochloric acid,
One or more in phosphoric acid, sulfuric acid, acetic acid, trifluoroacetic acid.
7. the preparation method of Rosuvastatin calcium impurities according to claim 4, it is characterised in that acidification reaction temperature-
20~40 DEG C；PH is 2~5 after acidifying；It is 5~20min to control the reaction time.
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