CN106749032B - A kind of preparation method of novel rosuvastain calcium intermediate - Google Patents
A kind of preparation method of novel rosuvastain calcium intermediate Download PDFInfo
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Abstract
The present invention provides a kind of preparation method of the rosuvastain calcium intermediate compound I of novel suitable industrial amplification production；This method is included under highly basic effect, and triphenylmethylphosphonium bromide phosphine is reacted with compound II, obtains intermediate compound I
Description
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of new preparation process of rosuvastain calcium intermediate.
Background technique
Rosuvastain calcium lists in the U.S. for the first time in 2003, is a kind of selectivity HMG-COA reductase inhibitor.It is clinical
Applied to cholesterinemia, hyperlipoproteinemia and atherosclerosis.Rosuvastain calcium (or CRESTOR), chemistry
Entitled (3R, 5S, 6E) -7- [4- (4- fluorophenyl) -6- isopropyl -2- (N- methyl-N-methanesulfonamide base) -5- pyrimidine] -3,5-
Dihydroxy -6- heptenoic acid calcium, structural formula are as follows:
(3R)-tert-butyl dimethylsilyloxy -5- oxo -6- triphenylphosphine alkene methyl caproate described in the present invention (is changed
Close object I), it is the key intermediate for preparing rosuvastain calcium.
The patent document JP 06135975 of Shionogi Seiyaku Kabushiki Kaisha reports the synthetic method of compound I at first, text
Middle use first is handled triphenylmethylphosphonium bromide phosphine through NaH-DMSO system, obtains Witting reagent, then obtain with carboxylic acid ester condensation
To compound I.Since NaH-DMSO system has some potential safety problems in the industrial production, and solvent DMSO boiling point is higher,
Difficulty is increased to solvent recovery and wastewater treatment, therefore the method used in the patent is difficult to apply in industrial production.
Subsequent document J.org.chem.Vol.59, No.25,7849-7854,1994 are referred to
Beginning material carrys out the method for prepare compound I, and route is as follows: route one
The route uses anhydride compound for starting material, and industrial market is difficult to obtain, and needs to leave away and come compared with macoradical
Activated ester intermediate is obtained, Atom economy is not met.
Patent document WO 2011141934 discloses another synthetic method, is made respectively with different mandelic acid acid esters
For starting material, intermediate X -1 is obtained under the action of n-BuLi with silylation acid anhydrides, then is purified through esterification, at salt, contracting
It closes reaction and obtains final finished.
It is more valuable that the route equally exists starting material, and uses in technique and arrive butyl lithium, the contour activation of sodium methoxide
Reagent is learned, certain security risk is brought to industrialized production.
It is disclosed in patent document WO 2011124050 using vinyl chloride as starting material, first obtains common intermediate III-
1, then through halogenated, the method for TEMPO oxidative synthesis J6, synthetic route is as follows:
Although the route uses more conventional R- epoxychloropropane as starting material, needs use NBS etc. compared with
Valuable halogenating agent first generates halides intermediate, then aoxidizes through TEMPO, is finally condensed to yield finished product with triphenylphosphine.Work
Sequence step is more, increases the difficulty for implementing industrialized production.
Patent document CN101735272 use intermediate compound III -1 same as route three, the route without
Halides intermediate, but carboxylic acid compound i.e. general formula compound III is obtained by potassium permanganate oxidation, but use in the route
Toxic articles methylchloroformate is reacted with compound III preparing activated ester intermediate, brings security risk to production and environment.
In conclusion there are reaction steps in above-mentioned each method, long, technique is related to toxic harmful chemical agents and rear place
Manage the problems such as cumbersome.Compared with prior art, technical advance of the invention is logical to prepare using entirely different method
Compound I is crossed, i.e., synthesizes compound I by preparing Compounds of formula II.Compared to said synthesis route, the method is not only reacted
Step is few, technique is environmentally protective and can in high yield, high-purity obtain product, be suitble to industrialized production.
Summary of the invention
Industrialized production, operation can be suitble to simple the object of the present invention is to provide one kind and the Rui Shu of relative inexpensiveness
Cut down the statin calcium intermediate i.e. preparation method of compound shown in general formula I.For this purpose, the invention adopts the following technical scheme:
Rosuvastain calcium intermediate i.e. compound of Formula I is prepared by Compounds of formula II,
Include the following steps: what the compound as shown in general formula II and triphenylmethylphosphonium bromide phosphine were formed under basic conditions
Witting reagent reacts to obtain；Wherein R is alkyl, and preferably R is the straight chain or cyclic alkyl of C1~C10.
Y is hydroxy-protective group, and preferably Y is t-Butyldimethylsilyl, benzyl or benzoyl.
Further, the preparation method of compound shown in rosuvastain calcium of the invention intermediate, that is, general formula I include with
Lower step:
(a) triphenylmethylphosphonium bromide phosphonate reagent is formed into Witting reagent under highly basic effect；
(b) Compounds of formula II is dissolved in organic solvent and is added in above-mentioned Witting reagent, it is anti-to carry out Witting
It answers, prepares compound of Formula I.
In post-processing, compound of Formula I can be obtained by Crystallization Separation on the basis of step (b).
Further, the range of choice of highly basic includes n-BuLi, hexyllithium, tert-butyl lithium, sodium hydrogen.Wherein, preferably just
Butyl lithium.
Further, the molar ratio of the highly basic and triphenylmethylphosphonium bromide phosphorus and Compounds of formula II is (2.0~3.0):
(2.0~3.0): 1.
Further, the highly basic and triphenylmethylphosphonium bromide phosphorus and Compounds of formula II preferred molar ratio (2.1~
2.5): (2.1~2.5): 1.
Further, organic solvent described in step (b) are as follows: methylene chloride, chloroform, tetrahydrofuran, methyl tertiary butyl ether(MTBE)
One of or arbitrary proportion mixed solvent.Wherein, preferred tetrahydrofuran.
Another aspect of the present invention additionally provides a kind of preparation method of Compounds of formula II comprising the steps of:
In Compounds of formula II, defined in the definition of R and Y and compound formula I identical.
Further, the preparation method of Compounds of formula II comprising the steps of:
(1) compound of formula III is dissolved in organic solvent, carbonyl dimidazoles is added and carry out condensation reaction.
(2) by upper step reaction solution, pass through Flash silica column separating purification product.
(3) organic solvent is removed, product i.e. Compounds of formula II is obtained.
Further, condensation reaction described in step (1) carries out between -30 DEG C~50 DEG C, preferably 0 DEG C~30 DEG C it
Between carry out, more preferably carried out between 20~25 DEG C.
Further, organic solvent described in step (1) is selected from methylene chloride, chloroform, methyl tertiary butyl ether(MTBE), tetrahydrofuran
One of or any two kinds of mixing.
Further, organic solvent described in step (1) is preferably methylene chloride.
Further, the molar ratio of compound III described in step (1) and carbonyl dimidazoles is 1:(1.0~2.0).
Further, the molar ratio of compound III described in step (1) and carbonyl dimidazoles be preferably 1:(1.0~
1.1)。
The preparation method of rosuvastain calcium intermediate, that is, general formula I provided by the invention is easy to operate, does not use in technique
Poisonous and harmful reagent, chemical reaction condition is mild, and the three wastes are easy to handle, relative inexpensiveness, and the finished product of high-purity can be obtained.
Specific embodiment
Below with reference to embodiment, the present invention is further elaborated, but these embodiments do not constitute any limit to the present invention
System.
Embodiment 1:(R)-methyl 3- (tertiary butyl dimethyl Si) -5- (1H- imidazoles -1- base) -5- oxopentanoic
The preparation of (compound II)
Compound III 30.0g 108.5mmol, methylene chloride 150ml are put into three mouthfuls of reaction flasks, dissolved clarification is stirred.Control
Carbonyl dimidazoles 18.5g 114.1mmol is added portionwise in 20~30 DEG C of temperature.It is stirred to react 2~3h, is controlled in sampling, until reaction solution
Residual quantity≤0.5% of middle compound III, reaction terminate.
Above-mentioned reaction solution addition Flash silica column was subjected to column purification, collects eluent.It is concentrated under reduced pressure and removes solvent, obtain
Yellow oil 31.9g.Yield 90.0%, GC purity are 95.0%.
Embodiment 2:(R)-methyl 3- (tertiary butyl dimethyl Si) -5- (1H- imidazoles -1- base) -5- oxopentanoic
The preparation of (compound II)
Compound III 30.0g 108.5mmol, methylene chloride 150ml are put into three mouthfuls of reaction flasks, dissolved clarification is stirred.Control
Carbonyl dimidazoles 35.2g 217.1mmol is added portionwise in 20~30 DEG C of temperature.It is stirred to react 2~3h, is controlled in sampling, until reaction solution
Residual quantity≤0.5% of middle compound III, reaction terminate.
Above-mentioned reaction solution addition Flash silica column was subjected to column purification, collects eluent.It is concentrated under reduced pressure and removes solvent, obtain
Yellow oil 34.0g.Pure yield 84.0%, GC purity are 88.0%.
Embodiment 3:(R)-methyl 3- (tertiary butyl dimethyl Si) -5- (1H- imidazoles -1- base) -5- oxopentanoic
The preparation of (compound II)
Compound III 30.0g 108.5mmol, methylene chloride 150ml are put into three mouthfuls of reaction flasks, dissolved clarification is stirred.Control
Carbonyl dimidazoles 40.5g 249.6mmol is added portionwise in 20~30 DEG C of temperature.It is stirred to react 2~3h, is controlled in sampling, until reaction solution
Residual quantity≤0.5% of middle compound III, reaction terminate.
Above-mentioned reaction solution addition Flash silica column was subjected to column purification, collects eluent.It is concentrated under reduced pressure and removes solvent, obtain
Yellow oil 34.5g.Pure yield 80.0%, GC purity are 83.0%.
Embodiment 4:(R)-methyl 3- (tertiary butyl dimethyl Si) -5- (1H- imidazoles -1- base) -5- oxopentanoic
The preparation of (compound II)
Compound III 30.0g, acetone 150ml are put into three mouthfuls of reaction flasks, dissolved clarification is stirred.20~30 DEG C of temperature control is in batches
Carbonyl dimidazoles 19.4g is added.Be stirred to react 2~3h, controlled in sampling, until reaction solution in compound III residual quantity≤
0.5%, reaction terminates.
By above-mentioned reaction solution evaporated under reduced pressure, residue addition Flash silica column was subjected to column purification, collects eluent.Subtract
Pressure concentration removes solvent, obtains yellow oil 30.0g.Yield 85.0%, GC purity are 93.5%.
Embodiment 5:(R)-methyl 3- (tertiary butyl dimethyl Si) -5- (1H- imidazoles -1- base) -5- oxopentanoic
The preparation of (compound II)
Compound III 30.0g, tetrahydrofuran 150ml are put into three mouthfuls of reaction flasks, dissolved clarification is stirred.20~30 DEG C of temperature control
Carbonyl dimidazoles 19.4g is added portionwise.It is stirred to react 2~3h, is controlled in sampling, up to the residual quantity of compound III in reaction solution
≤ 0.5%, reaction terminates.
Above-mentioned reaction solution addition Flash silica column was subjected to column purification, collects eluent.It is concentrated under reduced pressure and removes solvent, obtain
Yellow oil 32.3g.Yield 91.0%, GC purity are 98.0%.
Embodiment 6:(3R)-tert-butyl dimethylsilyloxy -5- oxo -6- triphenylphosphine alkene methyl caproate (compound I)
Preparation
By triphenylmethylphosphonium bromide phosphine 60.2g, tetrahydrofuran 400ml, dissolved clarification is stirred.- 40~-50 DEG C are cooled to, nitrogen
Protection is lower to be added dropwise concentration are as follows: 2.0mol/L n-butyllithium solution 84ml.Drop finishes, and insulation reaction 3~4 hours.Reaction solution is obtained to wait for
With.
The compound II 25.0g that embodiment 1 obtains is dissolved in tetrahydrofuran 100ml, is then added dropwise in above-mentioned reaction solution,
Temperature control is 2~3 hours cooling to -30~-40 DEG C of stirrings.
Reaction is finished, 0~-10 DEG C of dropwise addition 1N hydrochloric acid of temperature control, adjusts pH=6~7, and methyl tertiary butyl ether(MTBE) 300ml extraction point is added
Layer.15%KHSO is added dropwise in organic layer4Solution 83.0g, extracting and demixing.
Solution of potassium carbonate tune pH=8~9 are added in water layer, and methyl tertiary butyl ether(MTBE) 300ml extracting and demixing is added.Organic phase difference
With saturated sodium bicarbonate solution, saturated common salt water washing.It adds magnesium sulfate to be dried 2 hours, is filtered to remove desiccant, obtains
It is evaporated under reduced pressure to solution, obtains yellow oil.
It will obtain yellow oil to be dissolved in 50ml methyl tertiary butyl ether(MTBE), 0~10 DEG C of dropwise addition n-hexane 100ml of temperature control is stirred
Crystallization is mixed, is filtered, vacuum drying obtains off-white color crystal 16.0g.Yield 39.0%, HPLC purity are 99.5%.
Embodiment 7:(3R)-tert-butyl dimethylsilyloxy -5- oxo -6- triphenylphosphine alkene methyl caproate (compound I)
Preparation
By triphenylmethylphosphonium bromide phosphine 60.2g, tetrahydrofuran 400ml, dissolved clarification is stirred.- 40~-50 DEG C are cooled to, nitrogen
Protection is lower to be added dropwise concentration are as follows: 2.0mol/L tert .-butyllithium solution 85ml.Drop finishes, and insulation reaction 3~4 hours.Reaction solution is obtained to wait for
With.
The compound II 25.0g that embodiment 1 obtains is dissolved in tetrahydrofuran 100ml, is then added dropwise in above-mentioned reaction solution,
Temperature control is 2~3 hours cooling to -30~-40 DEG C of stirrings.
Reaction is finished, 0~-10 DEG C of dropwise addition 1N hydrochloric acid of temperature control, adjusts PH=6~7, and methyl tertiary butyl ether(MTBE) 300ml extraction point is added
Layer.15%KHSO is added dropwise in organic layer4Solution 83.0g, extracting and demixing.
Solution of potassium carbonate tune PH=8~9 are added in water layer, and methyl tertiary butyl ether(MTBE) 300ml extracting and demixing is added.Organic phase difference
With saturated sodium bicarbonate solution, saturated common salt water washing.It adds magnesium sulfate to be dried 2 hours, is filtered to remove desiccant, obtains
It is evaporated under reduced pressure to solution, obtains yellow oil.
It will obtain yellow oil to be dissolved in 50ml methyl tertiary butyl ether(MTBE), 0~10 DEG C of dropwise addition n-hexane 100ml of temperature control is stirred
Crystallization is mixed, is filtered, vacuum drying obtains off-white color crystal 14.9g.Yield 36.4%, HPLC purity are 99.6%.
Embodiment 8:(3R)-tert-butyl dimethylsilyloxy -5- oxo -6- triphenylphosphine alkene methyl caproate (compound I)
Preparation
By 50% sodium hydride 8.1g, tetrahydrofuran 400ml is stirred evenly.- 40~-50 DEG C are cooled to, is dripped under nitrogen protection
Add the tetrahydrofuran solution (60.2g+100ml) of triphenylmethylphosphonium bromide phosphine.Drop finishes, and insulation reaction 3~4 hours.It is reacted
Liquid is stand-by.
The compound II 25.0g that embodiment 1 obtains is dissolved in tetrahydrofuran 100ml, is then added dropwise in above-mentioned reaction solution,
Temperature control is 2~3 hours cooling to -30~-40 DEG C of stirrings.
Reaction is finished, 0~-10 DEG C of dropwise addition 1N hydrochloric acid of temperature control, adjusts pH=6~7, and methyl tertiary butyl ether(MTBE) 300ml extraction point is added
Layer.15%KHSO is added dropwise in organic layer4Solution 83.0g, extracting and demixing.
Solution of potassium carbonate tune pH=8~9 are added in water layer, and methyl tertiary butyl ether(MTBE) 300ml extracting and demixing is added.Organic phase difference
With saturated sodium bicarbonate solution, saturated common salt water washing.It adds magnesium sulfate to be dried 2 hours, is filtered to remove desiccant, obtains
It is evaporated under reduced pressure to solution, obtains yellow oil.
It will obtain yellow oil to be dissolved in 50ml methyl tertiary butyl ether(MTBE), 0~10 DEG C of dropwise addition n-hexane 100ml of temperature control is stirred
Crystallization is mixed, is filtered, vacuum drying obtains off-white color crystal 12.3g.Yield 30.0%, HPLC purity are 99.3%.
Above is only a specific embodiment of the present invention, but structure feature of the invention is not limited thereto, Ren Heben
Within the field of the present invention, made changes or modifications all cover within the protection scope of the present invention the technical staff in field.
Claims (3)
1. a kind of preparation method of rosuvastain calcium intermediate compound I,
R is methyl, and Y is t-Butyldimethylsilyl；It is characterized by:
This method is included under highly basic effect, and triphenylmethylphosphonium bromide phosphine is reacted with compound II, and reaction temperature is controlled -40
To -30 DEG C, intermediate compound I is obtained
The highly basic is n-BuLi,
The molar ratio of the highly basic and triphenylmethylphosphonium bromide phosphorus and Compounds of formula II is (2.1~2.5): (2.1~2.5):
1。
2. a kind of preparation method of novel rosuvastain calcium intermediate compound I according to claim 1, it is characterised in that:
Its reaction dissolvent range of choice includes tetrahydrofuran, acetone, methyl tertiary butyl ether(MTBE), toluene, methylene chloride.
3. a kind of preparation method of novel rosuvastain calcium intermediate compound I according to claim 2, it is characterised in that:
Its reaction dissolvent is preferably tetrahydrofuran.
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| CN108948078A (en) * | 2018-09-11 | 2018-12-07 | 浙江乐普药业股份有限公司 | A kind of synthetic method of rosuvastatin intermediate |
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| CN101735272B (en) * | 2009-12-11 | 2012-10-31 | 重庆博腾制药科技股份有限公司 | Method for preparing rosuvastatin calcium midbody |
| EP2383260A3 (en) * | 2010-04-30 | 2011-12-28 | Dipharma Francis S.r.l. | Process for the preparation of statins |
| CN102358747B (en) * | 2011-08-30 | 2012-09-19 | 浙江宏元药业有限公司 | Rosuvastatin calcium intermediate and method for preparing rosuvastatin calcium intermediate and rosuvastatin calcium |
| CN104016916A (en) * | 2014-05-16 | 2014-09-03 | 南通常佑药业科技有限公司 | Method for preparing intermediate of pitavastatin calcium |
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