CN101475558A - Preparation of rosuvastatin intermediate - Google Patents
Preparation of rosuvastatin intermediate Download PDFInfo
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- CN101475558A CN101475558A CNA2008102433172A CN200810243317A CN101475558A CN 101475558 A CN101475558 A CN 101475558A CN A2008102433172 A CNA2008102433172 A CN A2008102433172A CN 200810243317 A CN200810243317 A CN 200810243317A CN 101475558 A CN101475558 A CN 101475558A
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- rosuvastatin
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Abstract
The invention discloses a method for preparing a rosuvastatin intermediate. The method uses (4R)-cis-6-hydroxymethyl-2,2-dimethyl-1,3dioxan-4-terbutyl acetate serving as a substrate, hypervalent iodine reagent serving as an oxidizer to carry out a reaction in an environment of an organic solvent to obtain the rosuvastatin intermediate of (4R)-cis-6- formoxyl-2,2-dimethyl-1,3-dioxan-4- terbutyl acetate. Compared with the prior art, the method has the advantages of high yield, easy operation, mild conditions, small environment pollution, low cost and large-scale production.
Description
Technical field
The invention belongs to pharmacy field, be specifically related to a kind of Rosuvastatin intermediate (4R)-cis-6-formyl radical-2,2-dimethyl-1, the preparation method of 3-dioxane-4-tert.-butyl acetate.
Background technology
Rosuvastatin (ROSUVASTATIN) is blood fat reducing efficiently, is a kind of novel HMG-CoA reductase inhibitor, and its effect for reducing fat is big, uses separately the medicine that surpasses other Statins, is known as " super he spit of fland ".Because the little advantage of its high-efficiency low-toxicity side effect enjoy people's favor, so this medicine holds out broad prospects.
(4R)-cis-6-formyl radical-2; 2-dimethyl-1; 3 dioxanes-4-tert.-butyl acetate (1) is an important intermediate in synthesizing rosuvastatin spit of fland; the report of existing more synthetic method about it on the document; generally by (4R)-cis-6-methylol-2; 2-dimethyl-1,3 dioxane-4-tert.-butyl acetate (2) oxidation preparation.
Present oxygenated compound (2) prepares intermediate (1) method commonly used and is to use oxalyl chloride and dimethyl sulfoxide (DMSO) as oxygenant, as United States Patent (USP) U.S.Pat.No.4,970,313 just provide use oxalyl chloride and dimethyl sulfoxide (DMSO) to prepare the method for intermediate (1), but this method need be carried out under-78 ℃, and there is dimethyl sulphide to generate, is difficult for removing, influential to large-scale commercial production.
Summary of the invention
Technical problem to be solved by this invention provides a kind of Rosuvastatin intermediate (4R)-cis-6-formyl radical-2,2-dimethyl-1, and the new preparation method of 3-dioxane-4-tert.-butyl acetate (1), guaranteeing gentle reaction conditions, and relatively environmental protection.
For solving the problems of the technologies described above, the technical solution used in the present invention is as follows:
A kind of Rosuvastatin intermediates preparation; this method is with (4R)-cis-6-methylol-2; 2-dimethyl-1; 3 dioxanes-4-tert.-butyl acetate (2) is a substrate; with high iodine oxygenant is oxygenant, and in the organic solvent environment, reaction obtains Rosuvastatin intermediate (4R)-cis-6-formyl radical-2; 2-dimethyl-1,3-dioxane-4-tert.-butyl acetate (1).
Wherein, described high iodine oxygenant is neighbour-iodoxy phenylformic acid (3).
Wherein, described organic solvent is a polar solvent, for example, and second eyeball, acetone, N, dinethylformamide or dimethyl sulfoxide (DMSO).
Concrete reaction conditions is: the mol ratio of substrate and oxygenant is 1:1.0～2.0; The add-on of solvent is 3～12mL/g substrate; Temperature of reaction is 0～100 ℃, preferred 10～40 ℃; Reaction times is 0.5～5 hour.
Wherein, the adding mode of oxygenant can be disposable adding, also can divide many batches of addings, and every batch add-on, joining day do not require, and satisfies above-mentioned mol ratio condition as long as guarantee the oxygenant total amount.
Reaction formula is as follows:
Beneficial effect: method of the present invention compared with prior art, advantage is, the yield height is easy to operate, mild condition, environmental pollution is little, cost is lower, can scale operation.
Embodiment
According to following embodiment, the present invention may be better understood.Yet, those skilled in the art will readily understand that the described concrete material proportion of embodiment, processing condition and result thereof only are used to illustrate the present invention, and should also can not limit the present invention described in detail in claims.
Embodiment 1:
In there-necked flask, drop into (4R)-cis-6-methylol-2; 2-dimethyl-1; 3 dioxanes-4-tert.-butyl acetate (2.60g; 10.00mol), add dimethyl sulfoxide (DMSO) (10mL) stirring and dissolving, add neighbour-iodoxy phenylformic acid (3.00g in three batches; 10.70mol); be stirred to react completely (TLC tracking) under 25 ℃, about 1 hour, in reaction solution impouring water (40mL); extract with ethyl acetate (15mL * 2); merge organic phase, water (15mL * 2) washing, anhydrous magnesium sulfate drying; concentrate and remove ethyl acetate; get (4R)-cis-6-formyl radical-2,2-dimethyl-1,3 dioxane-4-tert.-butyl acetate 2.45g.
Embodiment 2:
In there-necked flask, drop into (4R)-cis-6-methylol-2; 2-dimethyl-1; (2.60g 10.00mol), adds N to 3 dioxanes-4-tert.-butyl acetate; dinethylformamide (20mL) stirring and dissolving; (4.20g 15.00mol), is stirred to react completely (TLC tracking) under 10 ℃ to add neighbour-iodoxy phenylformic acid in five batches; about 3 hours; in reaction solution impouring water (50mL),, merge organic phase with ethyl acetate (15mL * 2) extraction; water (20mL * 2) washing; anhydrous magnesium sulfate drying concentrates and removes ethyl acetate, gets (4R)-cis-6-formyl radical-2; 2-dimethyl-1,3-dioxane-4-tert.-butyl acetate 2.10g.
Embodiment 3:
In there-necked flask, drop into (4R)-cis-6-methylol-2; 2-dimethyl-1; 3 dioxanes-4-tert.-butyl acetate (2.60g; 10.00mol), add second eyeball (30mL) stirring and dissolving, add neighbour-iodoxy phenylformic acid (5.60g in six batches; 20.00mol); be stirred to react completely (TLC tracking) under 40 ℃, about 5 hours, in reaction solution impouring water (60mL); extract with ethyl acetate (15mL * 2); merge organic phase, water (25mL * 2) washing, anhydrous magnesium sulfate drying; concentrate and remove ethyl acetate; get (4R)-cis-6-formyl radical-2,2-dimethyl-1,3 dioxane-4-tert.-butyl acetate 2.30g.
Embodiment 4:
With the method for embodiment 1, different is that temperature of reaction is 0 ℃.
Embodiment 5:
With the method for embodiment 1, different is that temperature of reaction is 100 ℃.
Claims (6)
1, a kind of Rosuvastatin intermediates preparation; it is characterized in that this method is with (4R)-cis-6-methylol-2; 2-dimethyl-1; 3 dioxanes-4-tert.-butyl acetate is a substrate; with high iodine oxygenant is oxygenant, and in the organic solvent environment, reaction obtains Rosuvastatin intermediate (4R)-cis-6-formyl radical-2; 2-dimethyl-1,3-dioxane-4-tert.-butyl acetate.
2, Rosuvastatin intermediates preparation according to claim 1 is characterized in that described high iodine oxygenant is neighbour-iodoxy phenylformic acid.
3, Rosuvastatin intermediates preparation according to claim 1 is characterized in that described organic solvent is a polar solvent.
4, Rosuvastatin intermediates preparation according to claim 3 is characterized in that described organic solvent is second eyeball, acetone, N, dinethylformamide or dimethyl sulfoxide (DMSO).
5, according to any described Rosuvastatin intermediates preparation in the claim 1～4, the mol ratio that it is characterized in that substrate and oxygenant is 1:1.0～2.0, the add-on of solvent is 3～12mL/g substrate, and temperature of reaction is 0～100 ℃, and the reaction times is 0.5～5 hour.
6, Rosuvastatin intermediates preparation according to claim 5 is characterized in that temperature of reaction is 10～40 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008102433172A CN101475558A (en) | 2008-12-26 | 2008-12-26 | Preparation of rosuvastatin intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008102433172A CN101475558A (en) | 2008-12-26 | 2008-12-26 | Preparation of rosuvastatin intermediate |
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| Publication Number | Publication Date |
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| CN101475558A true CN101475558A (en) | 2009-07-08 |
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| CNA2008102433172A Pending CN101475558A (en) | 2008-12-26 | 2008-12-26 | Preparation of rosuvastatin intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014203045A1 (en) | 2013-06-20 | 2014-12-24 | Lupin Limited | A novel, green and cost effective process for synthesis of tert-butyl (3r,5s)-6-oxo-3,5-dihydroxy-3,5-o-isopropylidene-hexanoate |
-
2008
- 2008-12-26 CN CNA2008102433172A patent/CN101475558A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014203045A1 (en) | 2013-06-20 | 2014-12-24 | Lupin Limited | A novel, green and cost effective process for synthesis of tert-butyl (3r,5s)-6-oxo-3,5-dihydroxy-3,5-o-isopropylidene-hexanoate |
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Application publication date: 20090708 |