CN108707118A - A kind of preparation method of demethyl rosuvastain calcium - Google Patents
A kind of preparation method of demethyl rosuvastain calcium Download PDFInfo
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- CN108707118A CN108707118A CN201810651558.4A CN201810651558A CN108707118A CN 108707118 A CN108707118 A CN 108707118A CN 201810651558 A CN201810651558 A CN 201810651558A CN 108707118 A CN108707118 A CN 108707118A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Abstract
The invention discloses a kind of preparation methods of demethyl rosuvastain calcium, pass through the analysis to electronics cloud environment in reactant molecule, it develops using Formula II compound as raw material, first introduce benzyl, it restores, chloro then removes benzyl, the new method of demethyl rosuvastain calcium is prepared at triphenylphosphine salt, then by the reactions such as being condensed；The preparation method, pass through the introducing of benzyl, change molecular electronic environment, it is not only smoothed out the reduction reaction of compound IV, and makes reduzate V solidifications, conducive to isolating and purifying for later stage, therefore, the route reaction high income, simply and easily, prepared by the batch for being more suitable for demethyl rosuvastain calcium for post-processing.
Description
Technical field
The present invention relates to technical field of medicine synthesis, and in particular to a kind of preparation method of demethyl rosuvastain calcium
Background technology
Rosuvastain calcium is a kind of selective HMG-CoA reductase inhibitor, is developed by Astrazeneca AB,
It is listed in multiple countries and regions such as the U.S., Japan, Europe, China, since its curative effect of medication is better than other statins listed
Class drug, therefore it is known as " superstatin ".Domestic have a Nanjing first sign at present, composite tablet, honest multiple company's quilts such as to become a fine day
State Food and Drug Administration ratifies, and copies production.
Demethyl rosuvastain calcium shown in Formulas I, as the catabolite of rosuvastain calcium, not only for Rui Shuta
The quality control of spit of fland calcium has very big meaning, and can be used in the production of rosuvastain calcium controlling, impurity it is qualitative
And quantitative analysis, it can also be used to which the registration of rosuvastain calcium is declared.
Up to now, only one report (WO0185702) prepared about demethyl rosuvastain calcium, in the patent
In the synthetic route of report, multistep product is grease, the mode of column chromatography can only be used to be isolated and purified.Also, according to
The patent report finds second step reduction reaction, reaction system is extremely complex, does not lead substantially when repeating the operation
Product is wanted, and can only be carried out sub-argument purifying by way of multiple column chromatography, lead to demethyl rosuvastain calcium synthetic route
Total recovery it is very low.
The quality requirement of imitation medicine is continuously improved in view of current China, demethyl rosuvastain calcium is in Rosuvastatin
Significant, and the report synthetic route of demethyl rosuvastain calcium of calcareous amount control aspect, it is low that there are still yields, hardly possible point
From purifying, be not suitable for the problem of prepared by batch, therefore the synthetic route for developing a new demethyl rosuvastain calcium is ten
Divide necessary.
Invention content
Technical problem to be solved by the invention is to provide a kind of reaction yield height, post-processing simply and easily, is suitble to criticize
Measure the preparation method of the demethyl rosuvastain calcium of synthesis.
In order to solve the above technical problems, the technical scheme is that：A kind of preparation side of demethyl rosuvastain calcium
Method includes the following steps：
Step 1, under alkaline condition, Formula II compound is reacted with p-methyl benzene sulfonic chloride and Methanesulfomide, obtains compound
III；
Step 2, under alkaline condition, formula III compound is reacted with benzyl chloride, through recrystallization, obtains compound IV；
Step 3, under inert environments, compound IV is restored through DIBAL-H, through recrystallization, obtains compound V；
Step 4, under inert environments, compound V is reacted with thionyl chloride, obtains compound VI；
Step 5, compound VI deprotections, obtains compound VII；
Step 6, under inert environments, compound VII is reacted with triphenylphosphine, and filtering obtains compound VIII；
Step 7, under alkaline condition, compound VIII is condensed with compound IX, obtains compound X；
Step 8, under acid condition, the bis- hydroxyl protection bases hydrolysis of compound X obtain compound XI；
Step 9, under alkaline condition, compound XI hydrolysis of ester group then obtains target compound with calcium chloride at calcium salt
I。
As a kind of perferred technical scheme, in the step 1 and step 2, reaction dissolvent is ether, tetrahydrochysene furan
It mutters, Isosorbide-5-Nitrae-dioxane, t-butyl methyl ether, dichloromethane, ethyl acetate, butyl acetate, acetonitrile, dimethyl sulfoxide (DMSO), N, N-
One or more kinds of mixed solvents in dimethylformamide, toluene, dimethylbenzene.
As a kind of perferred technical scheme, described Step 1: in step 2 and step 7, the alkaline condition is by alkali
Property substance provide, alkaline matter be organic base or inorganic base；The organic base is N, N- diisopropylethylamine, N, N- diisopropyls
Ethylenediamine, trimethylamine, dimethylamine, diethylamine, triethylamine, three positive amine, aniline, methylphenylamine, N, accelerine, pyridine
In one or more kinds of mixtures；The inorganic base is one in sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus
Kind or more than one mixture.
As a kind of perferred technical scheme, the inorganic base is potassium carbonate.
As a kind of perferred technical scheme, in the step 2, the solvent that recrystallization uses when handling is normal heptane
It is mixed with alcohol mixed solvent, n-hexane and alcohol mixed solvent, isopropyl ether and alcohol mixed solvent or methyl tertiary butyl ether and ethyl alcohol
Bonding solvent.
As a kind of perferred technical scheme, in the step 2, the solvent that recrystallization uses when handling is n-hexane
With alcohol mixed solvent, the volume ratio of n-hexane and ethyl alcohol is 1:10~1:30.
As a kind of perferred technical scheme, described Step 3: in step 4 and step 6, organic solvent be ether,
One or more kinds of mixed solvents of tetrahydrofuran, 1,4- dioxane, dichloromethane, toluene, dimethylbenzene.
As a kind of perferred technical scheme, in the step 3, when recrystallization processing the solvent that uses for isopropyl ether,
One or more kinds of mixed solvents of t-butyl methyl ether, dichloromethane, toluene, dimethylbenzene.
As a kind of perferred technical scheme, in the step 5, reaction dissolvent is methanol, ethyl alcohol, isopropanol, tetrahydrochysene
One or more kinds of mixed solvents in furans, 1,4- dioxane, N,N-dimethylformamide.
As a kind of perferred technical scheme, in the step 5, debenzylation reagent is Pd/C-H2Or Pd (OH)2/
C-H2System.
By adopting the above-described technical solution, a kind of preparation method of demethyl rosuvastain calcium, by reactant
The analysis of electronics cloud environment in molecule, develops using Formula II compound as raw material, first introduces benzyl, restore, and chloro is then gone
Benzyl prepares the new method of demethyl rosuvastain calcium at triphenylphosphine salt, then by the reactions such as being condensed；The preparation method,
By the introducing of benzyl, molecular electronic environment is changed, is not only smoothed out the reduction reaction of compound IV, and makes reduction
Product V solidifications, conducive to isolating and purifying for later stage, therefore, the route reaction high income, post-processing simply and easily, is more suitable for
It is prepared by the batch of demethyl rosuvastain calcium.
Specific implementation mode
With reference to embodiment, the present invention is further explained.In the following detailed description, it is only retouched by way of explanation
Certain exemplary embodiments of the present invention are stated.Undoubtedly, those skilled in the art will recognize, without departing from
In the case of the spirit and scope of the present invention, the described embodiments may be modified in various different ways.Therefore,
Description is regarded as illustrative in nature, and is not intended to limit the scope of the claims.
A kind of preparation method of demethyl rosuvastain calcium, includes the following steps：
Step 1, under alkaline condition, Formula II compound is reacted with p-methyl benzene sulfonic chloride and Methanesulfomide, obtains compound
III；
Step 2, under alkaline condition, formula III compound is reacted with benzyl chloride, through recrystallization, obtains compound IV；
Step 3, under inert environments, compound IV is restored through DIBAL-H, through recrystallization, obtains compound V；
Step 4, under inert environments, compound V is reacted with thionyl chloride, obtains compound VI；
Step 5, compound VI deprotections, obtains compound VII；
Step 6, under inert environments, compound VII is reacted with triphenylphosphine, and filtering obtains compound VIII；
Step 7, under alkaline condition, compound VIII is condensed with compound IX, obtains compound X；
Step 8, under acid condition, the bis- hydroxyl protection bases hydrolysis of compound X obtain compound XI；
Step 9, under alkaline condition, compound XI hydrolysis of ester group then obtains target compound with calcium chloride at calcium salt
I。
In the step 1 and step 2, reaction dissolvent is ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, tertiary butyl first
Base ether, dichloromethane, ethyl acetate, butyl acetate, acetonitrile, dimethyl sulfoxide (DMSO), n,N-Dimethylformamide, toluene, dimethylbenzene
In one or more kinds of mixed solvents.The preferred butyl acetate of reaction dissolvent and acetonitrile of the step 1；The step
The two preferred N,N-dimethylformamide of reaction dissolvent.
Step 1: in step 2 and step 7, the alkaline condition is provided by alkaline matter described, and alkaline matter is to have
Machine alkali or inorganic base；The organic base is N, N- diisopropylethylamine, N, N- diisopropyl ethylenediamines, trimethylamine, dimethylamine, two
Ethamine, triethylamine, three positive amine, aniline, methylphenylamine, N, it is one or more kinds of mixed in accelerine, pyridine
Close object；The inorganic base is one or more kinds of mixtures in sodium carbonate, potassium carbonate, sodium bicarbonate, saleratus.Institute
State the preferred potassium carbonate of inorganic base.
In the step 2, when recrystallization processing the solvent that uses be normal heptane with alcohol mixed solvent, n-hexane and
Alcohol mixed solvent, isopropyl ether and alcohol mixed solvent or methyl tertiary butyl ether and alcohol mixed solvent.In the step 2, weight
The volume ratio of the preferred n-hexane of solvent and alcohol mixed solvent used when crystallization treatment, n-hexane and ethyl alcohol is 1:10~1:
30。
Described Step 3: in step 4 and step 6, organic solvent is ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, two
One or more kinds of mixed solvents of chloromethanes, toluene, dimethylbenzene.The preferred toluene of organic solvent.
In the step 3, when recrystallization processing the solvent that uses for isopropyl ether, t-butyl methyl ether, dichloromethane,
One or more kinds of mixed solvents of toluene, dimethylbenzene.The preferred toluene of solvent used when recrystallization processing.
In the step 5, reaction dissolvent is methanol, ethyl alcohol, isopropanol, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, N, N-
One or more kinds of mixed solvents in dimethylformamide；Reaction dissolvent preferred alcohol.
In the step 5, debenzylation reagent is Pd/C-H2Or Pd (OH)2/C-H2System；It is preferred that Pd (OH)2/C-H2
System.
In step 8, the acid condition is provided by dilute hydrochloric acid or dilute sulfuric acid.
In step 9, the alkaline matter is provided by sodium hydroxide solution.
The detailed step of demethyl rosuvastain calcium preparation method is as follows：
The K of 32.2g compounds II, 19.9g is added in reaction bulb2CO3, p-methyl benzene sulfonic chloride and butyl acetate, be warming up to
40 DEG C are stirred to react 2h；Then Methanesulfomide 13.7g and K is added2CO3Powder 23g, system are warming up to back flow reaction 5h；It has reacted
Cheng Hou is added water quenching to system and goes out, the stirring of 5%NaOH solution is added, adds concentrated hydrochloric acid and is adjusted to neutrality；Stratification, liquid separation,
Water phase is extracted to no product residue with EA, merges organic phase, 52g formula III compounds are concentrated to give after dry.
By 7.34g formula IIIs compound, 4.12g K2CO3And 40mL DMF are added in reaction bulb, are warming up to 40 DEG C, are added
2.6g benzyl chlorides, stirring insulation reaction 1h；Hydration EA, liquid separation after stirring are added into system, water phase is extracted with EA, is associated with again
Machine phase, sodium sulphate drying, concentration obtain crude product after removing solvent.The crude product is used into n-hexane：Ethyl alcohol (1:15) it is recrystallized, is obtained
To formula IV compound 8.1g, yield 88.4%, HPLC purity 97.2%.1H NMR(400MHz,CDCl3)δ7.87–7.78(m,
2H), 7.36-7.22 (m, 7H), 4.72 (s, 1H), 4.63 (s, 1H), 3.88 (s, 3H), 3.43 (m, J=12.7Hz, 1H),
3.04 (s, 3H), 1.34 (s, 3H), 1.31 (s, 3H).13C NMR(100MHz,CDCl3)δ166.27,166.06,163.99,
161.98,154.61,154.57,136.43,131.60,131.54,130.95,130.93,128.69,128.34,128.25,
114.98,114.82,110.64,83.19,54.12,52.13,37.48,32.06,20.68,19.81。
7.2g formula IV compounds are placed in 60mL toluene, system is cooled to 10 DEG C hereinafter, 30g is added dropwise after stirring
The toluene solution of DABAL-H, temperature control reaction；Reaction is completed, and water is added into system, reaction is slowly quenched, after adding EA stirrings
Liquid separation, organic phase washed once with saturated salt solution, anhydrous sodium sulfate drying, concentration, and re crystallization from toluene obtains 6g Formula V chemical combination
Object, yield 88.8%, HPLC purity 97.7%.1H NMR(400MHz,CDCl3)δ7.96–7.75(m,2H),7.50–7.13(m,
7H), 4.77 (s, 1H), 4.68 (s, 1H), 4.60 (s, 2H), 3.44 (m, J=12.8Hz, 1H), 3.05 (s, 1H), 1.45 (s,
1H),1.34(s,3H),1.32(s,3H)；13C NMR(100MHz,CDCl3)δ163.10,162.64,153.59,152.75,
136.43,132.20,131.82,128.69,128.34,128.25,127.72,115.35,60.68,54.12,37.48,
32.85,20.68。
By 7.3g Formula V compounds, 70mL toluene and 0.073g DMF are placed in a reaction flask；N2Displacement, stirring, is heated to 85
DEG C, SOCl is added dropwise2Toluene (20mL) mixed liquor of (2.38g), temperature control reaction；Reaction is completed, and 40ml water is added in system cooling,
Stirring, liquid separation, under the extraction of water layer again with toluene, combining methylbenzene layer, with saturation NaHCO3PH to 8 is adjusted, liquid separation is dry, concentration
It is dry to obtain 7.5g Formula IV compounds.
4.5gVI compounds are added in there-necked flask, using 20mL ethyl alcohol as solvent, using the Pd (OH) of 0.45g 10%2-H2Body
System carries out debenzylation, and hydrogen balloon is accessed after vacuumizing, and reacts at room temperature 10h, and raw material reaction finishes, and system filtering, concentration obtains
To 3.2g Formula VII compounds.
By 3.5g VII compounds as in 35ml toluene systems, N2Protection, is stirred at room temperature；Triphenylphosphine is added dropwise
Toluene (40ml) mixed liquor of (6.85g)；Reaction about 2~3h raw materials reaction finishes；Filtering washs filter cake with toluene, and vacuum is dry
It is dry to obtain 4.8g white solid Formula VIII compounds, yield 91.5%, HPLC purity 98.1%.
By 5.2g VIII compounds, 2.58g IX compounds are placed in 60ml DMF, stirring, N2Protection, is warming up to 70 DEG C
1.88g K are added afterwards2CO3Solid；Reaction finishes, and system cooling, is added toluene and water, water layer are extracted with toluene, merges organic
Phase, saturated common salt water washing is dry, is concentrated to give 5.3g Formula X compounds.
50ml acetonitriles are added in 5.6g Formula X compounds, and 1N dilute hydrochloric acid 5ml are added dropwise at room temperature, have reacted, system Na2CO3
It is adjusted to neutrality, EA extractions are added；Water phase merges organic phase again with EA extractions three times to no material, dry, is concentrated to give 5.0g,
Formula XI compound.1H NMR(400MHz,CDCl3) δ 7.99-7.72 (m, 2H), 7.44-7.13 (m, 2H), 6.62 (dd, J=
30.1,1.9Hz, 1H), 6.17 (s, 1H), 4.39 (s, 1H), 4.31-4.08 (m, 1H), 3.86 (tt, J=13.0,11.4Hz,
1H), 3.42 (dt, J=25.4,12.8Hz, 1H), 2.94 (s, 3H), 2.91 (s, 1H), 2.71-2.60 (m, 2H), 2.46 (dd,
J=24.8,11.4Hz, 1H), 1.49 (m, 2H), 1.41 (s, 9H), 1.34 (s, 3H), 1.31 (s, 3H).13C NMR(100MHz,
CDCl3)δ173.63,161.50,159.90,153.54,145.33,132.18,131.71,129.13,118.67,115.53,
113.70,81.86,71.41,66.46,44.62,42.91,42.14,33.46,28.33,20.68。
5.2g Formula XI compounds are placed in there-necked flask, 50ml acetonitriles are added, 1N NaOH solutions are then added dropwise at room temperature
10ml, drop finish, and are reacted at room temperature to raw material without residue, and t-butyl methyl ether extraction is added in system, and liquid separation merges organic layer, drop
Add calcium chloride solution, stirs, rejection filter, rejection filter after solid is beaten with water, it is dry, obtain 9.8g target product I, yield 98%, HPLC
Purity 96.1%.1H NMR(400MHz,CDCl3) δ 8.08-7.66 (m, 2H), 7.48-7.13 (m, 2H), 6.63 (dd, J=
30.2,2.0Hz, 1H), 6.30-6.20 (m, 1H), 6.19 (s, 1H), 4.62 (s, 1H), 4.20 (qd, J=11.2,1.9Hz,
1H), 3.85 (tt, J=13.0,11.4Hz, 1H), 3.42 (dq, J=25.5,12.7Hz, 1H), 2.94 (s, 3H), 2.69 (s,
1H), 2.65 (dd, J=24.9,11.4Hz, 1H), 2.45 (dd, J=24.7,11.4Hz, 1H), 1.50 (ddd, J=13.0,
11.1,10.4Hz,1H),1.34(s,3H),1.31(s,3H)；13C NMR(100MHz,CDCl3)δ175.21,161.50,
159.90,153.54,145.33,132.18,131.71,129.13,118.67,115.53,113.70,71.41,65.31,
44.62,43.24,42.91,33.46,20.68。
The basic principles and main features and advantages of the present invention of the present invention have been shown and described above.The technology of the industry
Personnel are it should be appreciated that the present invention is not limited to the above embodiments, and the above embodiments and description only describe this
The principle of invention, without departing from the spirit and scope of the present invention, various changes and improvements may be made to the invention, these changes
Change and improvement all fall within the protetion scope of the claimed invention.The claimed scope of the invention by appended claims and its
Equivalent thereof.
Claims (10)
1. a kind of preparation method of demethyl rosuvastain calcium, which is characterized in that include the following steps：
Step 1, under alkaline condition, Formula II compound is reacted with p-methyl benzene sulfonic chloride and Methanesulfomide, obtains compound III；
Step 2, under alkaline condition, formula III compound is reacted with benzyl chloride, through recrystallization, obtains compound IV；
Step 3, under inert environments, compound IV is restored through DIBAL-H, through recrystallization, obtains compound V；
Step 4, under inert environments, compound V is reacted with thionyl chloride, obtains compound VI；
Step 5, compound VI deprotections, obtains compound VII；
Step 6, under inert environments, compound VII is reacted with triphenylphosphine, and filtering obtains compound VIII；
Step 7, under alkaline condition, compound VIII is condensed with compound IX, obtains compound X；
Step 8, under acid condition, the bis- hydroxyl protection bases hydrolysis of compound X obtain compound XI；
Step 9, under alkaline condition, compound XI hydrolysis of ester group then obtains target compound I with calcium chloride at calcium salt.
2. the preparation method of demethyl rosuvastain calcium as described in claim 1, which is characterized in that in the step 1 and
In step 2, reaction dissolvent be ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, t-butyl methyl ether, dichloromethane, ethyl acetate,
Butyl acetate, acetonitrile, one or more kinds of mixing in dimethyl sulfoxide (DMSO), n,N-Dimethylformamide, toluene, dimethylbenzene
Solvent.
3. the preparation method of demethyl rosuvastain calcium as described in claim 1, which is characterized in that described Step 1:
In step 2 and step 7, the alkaline condition is provided by alkaline matter, and alkaline matter is organic base or inorganic base；It is described organic
Alkali is N, N- diisopropylethylamine, N, N- diisopropyl ethylenediamines, trimethylamine, dimethylamine, diethylamine, triethylamine, three positive amine, benzene
Amine, methylphenylamine, N, one or more kinds of mixtures in accelerine, pyridine；The inorganic base is carbonic acid
One or more kinds of mixtures in sodium, potassium carbonate, sodium bicarbonate, saleratus.
4. the preparation method of demethyl rosuvastain calcium as claimed in claim 3, which is characterized in that the inorganic base is carbon
Sour potassium.
5. the preparation method of demethyl rosuvastain calcium as described in claim 1, which is characterized in that in the step 2
In, when recrystallization processing the solvent that uses be normal heptane with alcohol mixed solvent, n-hexane and alcohol mixed solvent, isopropyl ether and
Alcohol mixed solvent or methyl tertiary butyl ether and alcohol mixed solvent.
6. the preparation method of demethyl rosuvastain calcium as claimed in claim 5, which is characterized in that in the step 2
In, for the solvent that recrystallization uses when handling for n-hexane and alcohol mixed solvent, the volume ratio of n-hexane and ethyl alcohol is 1:10~
1:30。
7. the preparation method of demethyl rosuvastain calcium as described in claim 1, which is characterized in that described Step 3:
In step 4 and step 6, organic solvent is ether, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, dichloromethane, toluene, dimethylbenzene
One or more kinds of mixed solvents.
8. the preparation method of demethyl rosuvastain calcium as described in claim 1, which is characterized in that in the step 3
In, the solvent that recrystallization uses when handling is isopropyl ether, t-butyl methyl ether, dichloromethane, toluene, one kind of dimethylbenzene or one
Kind or more mixed solvent.
9. the preparation method of demethyl rosuvastain calcium as described in claim 1, which is characterized in that in the step 5
In, reaction dissolvent is one kind in methanol, ethyl alcohol, isopropanol, tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, n,N-Dimethylformamide
Or more than one mixed solvent.
10. the preparation method of demethyl rosuvastain calcium as described in claim 1, which is characterized in that in the step 5
In, debenzylation reagent is Pd/C-H2Or Pd (OH)2/C-H2System.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040006097A1 (en) * | 2000-05-10 | 2004-01-08 | Hill Steven James | (E)-7(4-Fluorophenyl)-6isopropyl2-mesylaminopyrimidin-5-y)-(3r,5s)-dihydroxyhept-6-enoic acid. |
| CN101376647A (en) * | 2007-08-31 | 2009-03-04 | 中山奕安泰医药科技有限公司 | Method for synthesizing rosuvastatin intermediate and rosuvastatin |
| CN101792411A (en) * | 2010-03-26 | 2010-08-04 | 常州晟永光电材料有限公司 | New method for combining ethyl sulfonamide |
| CN105175346A (en) * | 2015-05-19 | 2015-12-23 | 南京博优康远生物医药科技有限公司 | Method for synthesis of rosuvastatin calcium intermediate |
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2018
- 2018-06-22 CN CN201810651558.4A patent/CN108707118A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040006097A1 (en) * | 2000-05-10 | 2004-01-08 | Hill Steven James | (E)-7(4-Fluorophenyl)-6isopropyl2-mesylaminopyrimidin-5-y)-(3r,5s)-dihydroxyhept-6-enoic acid. |
| CN101376647A (en) * | 2007-08-31 | 2009-03-04 | 中山奕安泰医药科技有限公司 | Method for synthesizing rosuvastatin intermediate and rosuvastatin |
| CN101792411A (en) * | 2010-03-26 | 2010-08-04 | 常州晟永光电材料有限公司 | New method for combining ethyl sulfonamide |
| CN105175346A (en) * | 2015-05-19 | 2015-12-23 | 南京博优康远生物医药科技有限公司 | Method for synthesis of rosuvastatin calcium intermediate |
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| Title |
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| 刘鹰翔: "《药物合成反应》", 31 August 2017 * |
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