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CN104447784A - Statin medicine intermediate as well as preparation method and application thereof - Google Patents

Statin medicine intermediate as well as preparation method and application thereof Download PDF

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CN104447784A
CN104447784A CN201410720698.4A CN201410720698A CN104447784A CN 104447784 A CN104447784 A CN 104447784A CN 201410720698 A CN201410720698 A CN 201410720698A CN 104447784 A CN104447784 A CN 104447784A
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cyclohexanedione
general formula
molar ratio
preparation
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CN104447784B (en
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罗煜
丁时澄
瞿旭东
孙传明
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Ecolab Biotechnology Shanghai Co Ltd
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NANJING ABIOCHEM BIOLOGICAL PHARMACEUTICAL TECHNOLOGY Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems
    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

The invention discloses a compound which can be used as a statin medicine intermediate and has a structure shown in a general formula I, and a preparation method and application of the compound. According to the compound disclosed by the invention, by introducing cyclohexanedione, a bimolecular intermediate can be produced by virtue of one-step reaction, the purpose that the statin medicine intermediate with high yield and environment-friendly performance is prepared by using cheap and easily-available raw materials can be achieved, and the compound is more suitable for the implementation of industrial production.

Description

Statin drug intermediate and preparation method and application thereof
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a statin intermediate, a preparation method and application thereof, in particular to a compound shown as a general formula I, and a preparation method and application thereof.
Background
Statins are hydroxymethylglutaryl-coenzyme a (HMG-CoA) reductase inhibitors that block the intracellular mevalonate metabolic pathway by competitively inhibiting endogenous cholesterol synthesis rate-limiting enzyme (HMG-CoA) reductase, resulting in a decrease in intracellular cholesterol synthesis, which in turn feedback stimulates an increase in the number and activity of low density lipoprotein receptors on the cell membrane surface (mainly hepatocytes), resulting in an increase in serum cholesterol clearance and a decrease in levels. Statins also inhibit the synthesis of apolipoprotein B-100 by the liver, thereby reducing the synthesis and secretion of triglycerides-rich AV, lipoproteins. Therefore, the statins are called magical drugs in the aspect of reducing blood fat.
General formula (VII)The compound is an important intermediate for artificially synthesizing statins, such as rosuvastatin, atorvastatin, pravastatin, pitavastatin, fluvastatin, lovastatin and the like. At present, many researches and some related reports have been made on the synthesis of the compound with the general formula, but the methods have obvious defects. For example, Chinese patent CN1662520B discloses a method represented by the following general formulaThe compound (M represents H, alkali metal or alkaline earth metal) is contacted with acyl chloride reagent in inert solvent to form corresponding acyl chloride, and then reacted with alcohol in the presence of N-morpholine to generate the product. The reported yield of the method can reach 80-90%, but the applicant finds that the yield is low and is only about 10% through a plurality of experiments, and the method uses an acyl chlorination reagent, so that the reaction is violent, and byproducts are more, so that the method is not suitable for large-scale reaction. As another example, Chinese patent CN100378091C discloses a method represented by the following general formulaThe compound is used as raw material and reacts with acetalization reagent in the presence of acid catalyst. This method also has a problem that the reaction yield is low, and R is hardly formed due to steric hindrance or the like1Esters having more than 3 carbon atoms in the position.
Disclosure of Invention
The invention aims to provide a novel statin intermediate, a preparation method and application thereof. By introducing cyclohexanedione in the preparation, the invention can generate a bimolecular intermediate through one-step reaction, can realize the purpose of preparing the statin intermediate by using cheap and easily obtained raw materials and having high yield and environmental friendliness, and is more suitable for industrial production.
In order to achieve the above object, the present invention provides the following technical solutions.
The first aspect of the invention provides a compound which can be used as a statin intermediate and has a structure shown in a general formula I:
wherein,
x is selected from the group consisting of a leaving group, azido, -CN, -OH, -OCOR1、-COOR1、-NH2、-NHR1or-CHO;
r and R1Each independently represents an ester residue.
In the above compounds, the leaving group may be selected from the following groups: halogen, such as Cl, Br or I; a tosylate group; a methanesulfonyl group; an acyloxy group, preferably an acyloxy group having 1 to 6 carbon atoms, particularly an acetoxy group; a phenylacetoxy group; alkoxy, preferably alkoxy having 1 to 6 carbon atoms; (hetero) aryloxy groups, preferably (hetero) aryloxy groups having 6 to 12 carbon atoms.
R1Selected from ester residues, preferably alkyl groups having 1 to 6 carbon atoms, or aryl groups having 6 to 12 carbon atoms, more preferably methyl, ethyl, propyl, isobutyl or tert-butyl.
Preferably, X is selected from Cl, azido, Z,-CN、-OH、-OCOCH3。
R is selected from ester residues, preferably alkyl groups such as those having 1 to 6 carbon atoms, or aryl groups such as those having 8 to 12 carbon atoms, more preferably methyl, ethyl, propyl, isobutyl or tert-butyl groups, particularly preferably methyl or tert-butyl groups.
In a second aspect, the present invention provides a method for preparing a compound represented by the above general formula I, wherein: reacting a compound shown as a general formula II with 1, 4-cyclohexanedione in a solvent;
wherein X has the same definition as X in formula I.
In the above preparation method, the compound represented by the general formula II is reacted with 1, 4-cyclohexanedione in a suitable solvent selected from toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetonitrile, methanol, ethanol, etc.
The reaction is preferably carried out at 0 to 80 ℃, more preferably at 20 to 35 ℃.
Preferably, the reaction system is carried out under the action of a ketocarbonyl protecting agent selected from trimethyl orthoformate, triethyl orthoformate, tetramethyl orthocarbonate, tetraethyl orthocarbonate, trimethyl orthoacetate or triethyl orthoacetate and an acid catalyst; the acid catalyst is selected from p-toluenesulfonic acid and methanesulfonic acid.
Preferably, the molar ratio of the compound of the general formula II to the 1, 4-cyclohexanedione is 2-10:1, more preferably 2-3: 1.
Preferably, the molar ratio of the 1, 4-cyclohexanedione to the ketone carbonyl protecting agent is from 1:2 to 10, more preferably from 1:2 to 3.
Preferably, the molar ratio of the 1, 4-cyclohexanedione to the acid catalyst is from 1:0.001 to 0.1, more preferably from 1:0.02 to 0.05.
In a third aspect, the present invention provides another process for preparing a compound represented by the above general formula I, which comprises: reacting a compound shown as a general formula III with 1, 4-cyclohexanedione in a solvent;
wherein X and R have the same meanings as X and R in the formula I, respectively.
In the above preparation method, the compound represented by the general formula III is reacted with 1, 4-cyclohexanedione in a suitable solvent selected from toluene, dichloromethane, tetrahydrofuran, acetonitrile, methanol, ethanol, etc.
The reaction is preferably carried out at 0 to 80 ℃, more preferably at 20 to 35 ℃.
Preferably, the reaction system is carried out under the action of a catalyst selected from p-toluenesulfonic acid and methanesulfonic acid.
Preferably, the molar ratio of the compound in the general formula III to the 1, 4-cyclohexanedione is 2-10: 1; more preferably 2-3: 1.
Preferably, the molar ratio of the 1, 4-cyclohexanedione to the catalyst is from 1:0.001 to 0.1, more preferably from 1:0.02 to 0.05.
In both of the preparation methods disclosed herein, the starting materials used are known compounds in the art, and may be obtained commercially or synthesized by preparation methods known in the art.
The fourth aspect of the invention is to provide the application of the compound shown in the general formula I in preparing statins.
Compared with the prior art, the invention provides a brand-new statin intermediate, namely the compound shown in the general formula I. By introducing cyclohexanedione, the invention can generate a bimolecular intermediate through one-step reaction, can realize the purpose of preparing the statin intermediate by using cheap and easily available raw materials and having high yield and environmental friendliness, and is more suitable for industrial production.
Detailed Description
The present invention will be described in further detail with reference to examples, but it should not be construed as limiting the scope of the present invention.
Example 1
1, 4-cyclohexanedione (10.0g) was dissolved in 100mL of toluene, and trimethyl orthoformate (19.8g) and p-toluenesulfonic acid (0.46g) were added with stirring at room temperature, followed by stirring for 1 hour, 6-chloromethyl-4-hydroxy-tetrahydropyran-2-one (30.0g) was added, and the reaction was continued with stirring for 1 hour. Pouring the reaction solution into sodium bicarbonate aqueous solution, extracting twice with toluene, combining organic phases, washing once with saturated salt solution, drying with sodium sulfate, and concentrating and performing dry column chromatography to obtain 33.5g of a target product with the molar yield of 80%.
The structure of the product was confirmed by hydrogen nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy.
1H NMR(300MHz,CDCl3):4.53-4.62(1H,m),4.31-4.40(1H,m),3.95-4.15(2H,m),3.68(3H,s),3.66(3H,s),3,44-3.56(4H,m),2.35-2.65(4H,m),1.22-2.08(12H,m)。
MS(ESI)m/z：(M+H)＝469.1。
Example 2
1, 4-cyclohexanedione (12.0g) was dissolved in 120mL of dichloromethane, and trimethyl orthoformate (23.8g) and p-toluenesulfonic acid (0.46g) were added with stirring at room temperature, followed by stirring for 1 hour, and 6-azidomethyl-4-hydroxy-tetrahydropyran-2-one (40.2g) was added and the reaction was continued with stirring for 1 hour. Pouring the reaction solution into sodium bicarbonate aqueous solution, extracting twice with toluene, combining organic phases, washing once with saturated salt solution, drying with sodium sulfate, and concentrating and performing dry column chromatography to obtain 40.2g of a target product with the molar yield of 78%.
The structure of the product was confirmed by hydrogen nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy.
1H NMR(300MHz,CDCl3):4.48-4.57(1H,m),4.30-4.43(1H,m),3.91-4.12(2H,m),3.64(3H,s),3.61(3H,s),2.32-2.64(4H,m),1.19-2.04(16H,m)。
MS(ESI)m/z：(M+H)＝483.2。
Example 3
1, 4-cyclohexanedione (15.0g) was dissolved in 150mL of tetrahydrofuran, and triethyl orthoformate (42.3g) and p-toluenesulfonic acid (0.67g) were added with stirring at room temperature, followed by stirring for 1 hour, 6-cyanomethyl-4-hydroxy-tetrahydropyran-2-one (44.3g) was added, and the reaction was continued with stirring for 1 hour. Pouring the reaction solution into sodium bicarbonate aqueous solution, extracting twice with toluene, combining organic phases, washing once with saturated salt solution, drying with sodium sulfate, and concentrating and performing dry column chromatography to obtain 50.9g of a target product with the molar yield of 82%.
The structure of the product was confirmed by hydrogen nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy.
1H NMR(300MHz,CDCl3):；4.56-4.68(1H,m),4.31-4.40(1H,m),4.13(2H,q),3.44-3.56(4H,m),2.35-2.65(8H,m),1.21-2.06(18H,m)。
MS(ESI)m/z：(M+H)＝479.2。
Example 4
1, 4-cyclohexanedione (10.0g) was dissolved in 100mL of toluene, methanesulfonic acid (0.21g) and methyl 6-chloro-3, 5-dihydroxy-hexanoate (38.4g) were added with stirring at room temperature, and the reaction was continued for 1 hour with stirring. Pouring the reaction solution into sodium bicarbonate aqueous solution, extracting twice with toluene, combining organic phases, washing once with saturated salt solution, drying with sodium sulfate, and concentrating and performing dry column chromatography to obtain the target product 34.7g with the molar yield of 83%.
The structure of the product was confirmed by hydrogen nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy.
1H NMR(300MHz,CDCl3):4.53-4.62(1H,m),4.31-4.40(1H,m),3.95-4.15(2H,m),3.68(3H,s),3.66(3H,s),3,44-3.56(4H,m),2.35-2.65(4H,m),1.22-2.08(12H,m)。
MS(ESI)m/z：(M+H)＝469.1。
Example 5
1, 4-cyclohexanedione (15.0g) was dissolved in 150mL of dichloromethane, p-toluenesulfonic acid (0.53g) and tert-butyl 6-acetoxy-3, 5-dihydroxy-hexanoate (73.4g) were added with stirring at room temperature, and the reaction was continued with stirring for 1 hour. Pouring the reaction solution into sodium bicarbonate aqueous solution, extracting twice with toluene, combining organic phases, washing once with saturated salt solution, drying with sodium sulfate, and concentrating and performing dry column chromatography to obtain 60.3g of a target product with the molar yield of 75%.
The structure of the product was confirmed by hydrogen nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy.
1H NMR(300MHz,CDCl3):4.21-4.3(1H,m),4.03-4.2(1H,m),3.92-4.13(2H,m),3.15(4H,s),2.31-2.62(4H,m),2.06-2.17(6H,s),1.5-1.82(8H,m),1.43(18H,s),1.20-2.05(4H,m)。
MS(ESI)m/z：(M+H)＝601.3。
Example 6
4g of the product obtained in example 5 was dissolved in 20mL of anhydrous methanol, 2g of potassium carbonate was added, reflux reaction was carried out for 4 to 8 hours, the reaction was completed, filtration was carried out, the filter cake was washed with methanol, the filtrate was washed once with a saturated saline solution, dried over sodium sulfate, and concentrated to dry column chromatography to obtain 2.96g of the objective product with a molar yield of 86%.
The structure of the product was confirmed by hydrogen nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy.
1H NMR(300MHz,CDCl3):；4.43(2H,m),3.88(2H,m),3.54-3.79(4H,d),2.26-2.51(4H,d),2.0(2H,s),1.58-1.83(8H,t),1.48-1.73(4H,dd),1.40(18H,s)。
MS(ESI)m/z：(M+H)＝517.2。
Example 7
1, 4-cyclohexanedione (10.0g) was dissolved in 100mL of tetrahydrofuran, and p-toluenesulfonic acid (0.37g) and ethyl 6-cyano-3, 5-dihydroxy-hexanoate (37.7g) were added with stirring at room temperature, and the reaction was continued for 1 hour with stirring. Pouring the reaction solution into sodium bicarbonate aqueous solution, extracting twice with toluene, combining organic phases, washing once with saturated salt solution, drying with sodium sulfate, and concentrating and performing dry column chromatography to obtain the target product 36.3g with the molar yield of 85%.
The structure of the product was confirmed by hydrogen nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy.
1H NMR(300MHz,CDCl3):4.43(2H,m),3.8(2H,m),4.12(2H,q),2.41-2.66(4H,d),2.26-2.51(4H,d),1.58-1.83(8H,t),1.48-1.73(4H,dd),1.3(6H,t)。
MS(ESI)m/z：(M+H)＝479.2。
EXAMPLE 8 Synthesis of rosuvastatin calcium
1) The method comprises the following steps: conversion of alcohols to aldehydes
Adding 250mL of dichloromethane and 10mL of oxalyl chloride into a 500mL reaction bottle, carrying out nitrogen protection, cooling to-70 ℃, dropwise adding 11.5mL of dimethyl sulfoxide, carrying out heat preservation for 10 minutes after adding, then dropwise adding 20mL of dichloromethane solution containing 13.5g of alcohol raw material shown in the reaction formula at the temperature, carrying out heat preservation for 30 minutes after adding for 10 minutes, then dropwise adding 9mL of triethylamine at the temperature, and carrying out heat preservation for 30 minutes after adding; the reaction was poured into 100mL of water and stirred for 5 minutes, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed once with 80mL of 1N hydrochloric acid, once with 5% sodium bicarbonate, once with water, dried over anhydrous sodium sulfate and concentrated to remove the solvent, to give 13g of a colorless oil, which gave an aldehyde in 97% yield.
The structure of the product was confirmed by nmr hydrogen spectroscopy.
1H NMR(300MHz,CDCl3):9.7(1H)9.5(1H),4.31-4.2(1H,m),4.08-4.25(1H,m),3.9-4.18(2H,m),2.4-2.57(4H,m),2.03-2.2(6H,s),1.5-1.82(8H,m),1.43(18H,s),1.20-2.05(4H,m)。
2) Step two: the aldehyde being bound to the mother nucleus
17.2g of aldehyde (the compound represented by the first chemical structural formula in the above reaction formula, i.e., the product of step one), 50g of mother nucleus (the compound represented by the second chemical structural formula in the above reaction formula) and 400mL of acetonitrile were charged into a 500mL four-necked flask, heated to 70 ℃ and stirred until dissolved, and then the heating was stopped, and 2.75g of 60% sodium hydride was added and reacted for 60 minutes. Pouring the reaction solution into ice water, extracting with ethyl acetate, washing an organic phase with water, drying with anhydrous sodium sulfate, concentrating a solvent, adding 400mL of ethanol, slowly cooling to 0 ℃ for crystallization to obtain a crude product, then recrystallizing with 350mL of ethanol, and drying to obtain 30g of a white solid with the purity of 99% and the yield of 78%.
The structure of the product was confirmed by nmr hydrogen spectroscopy.
1H NMR(300MHz,CDCl3):7.68(4H,m)，7.13(4H,m),6.56(2H,m),5.5(2H,m),4.31-4.2(1H,m),4.08-4.25(1H,m),3.9-4.18(2H,m),2.4-2.57(4H,m),2.03-2.2(6H,s),1.5-1.82(8H,m),1.43(18H,s),1.20-2.05(4H,m)。
3) Step three: preparation of rosuvastatin calcium salt
Adding 200mL of tetrahydrofuran and 32.4g of the product of the second step into a reaction bottle, stirring for dissolving, dropwise adding 15mL of 2N hydrochloric acid at 25 ℃, stirring for reacting for 5h, carrying out TLC detection after complete reaction and carrying out reduced pressure concentration, adding 100mL of water, extracting with ethyl acetate, combining organic phases, drying with sodium sulfate, filtering, dissolving the filtrate in 500mL of methanol after carrying out reduced pressure concentration, adding 50mL of 5% sodium hydroxide solution, stirring for reacting for 6h at 40 ℃, carrying out reduced pressure concentration after finishing reaction to remove methanol, adding water, washing an aqueous phase with methyl tert-butyl ether, filtering to remove insoluble substances, and cooling to 20 ℃. And 6mL of 0.5g/mL calcium acetate solution is dropwise added into the solution, the solution is stirred for 30 minutes after the dropwise addition, the solution is filtered, a filter cake is washed twice by water and dried to obtain 22g of a product, and the yield is 81%.
The structure of the product was confirmed by hydrogen nuclear magnetic resonance spectroscopy and electrospray ionization mass spectroscopy.
1H NMR(300MHz,CDCl3):7.71(2H,dd),7.14(2H,t),6.63(1H,dd),5.56(1H,dd),4.39(1H,m),4.12(1H,m),3.54(3H,s),3.51(3H,s),3.47(1H,m),2.44(1H,dd),2.33(1H,dd),1.67(1H,dt),1.52(1H,dt),1.27(6H,d)。
MS(ESI)m/z：1001.3(M+H)+。
In conclusion, the invention introduces 1, 4-cyclohexanedione, utilizes cheap and easily available raw materials, can obtain a brand-new bimolecular statin intermediate, namely the compound shown in the general formula I, in a high yield and in an environment-friendly way through one-step reaction, and is more suitable for industrial production.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the present invention. Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims.

Claims (19)

1. A compound having the structure shown in formula I:
wherein,
x is selected from the group consisting of a leaving group, azido, -CN, -OH, -OCOR1、-COOR1、-NH2、-NHR1or-CHO;
r and R1Each independently represents an ester residue.
2. The compound of claim 1, wherein: the leaving group is selected from halogen, tosylate, mesyl, acyloxy, phenylacetyloxy, alkoxy, or (hetero) aryloxy.
3. The compound of claim 1, wherein: r1Selected from alkyl groups having 1 to 6 carbon atoms or aryl groups having 6 to 12 carbon atoms, preferably methyl, ethyl, propyl, isobutyl or tert-butyl.
4. The compound of claim 1, wherein: x is selected from Cl, azido, -CN, -OH, or-OCOCH3。
5. The compound of claim 1, wherein: r is selected from alkyl groups having 1 to 6 carbon atoms or aryl groups having 8 to 12 carbon atoms.
6. The compound of claim 1, wherein: r is selected from methyl, ethyl, propyl, isobutyl or tert-butyl, preferably methyl or tert-butyl.
7. A process for the preparation of a compound as claimed in claims 1 to 6, characterized in that: reacting a compound shown as a general formula II with 1, 4-cyclohexanedione in a solvent;
wherein X has the same definition as X in formula I.
8. The method of claim 7, wherein: the solvent is selected from toluene, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, acetonitrile, methanol or ethanol.
9. The method of claim 7, wherein: the reaction system is carried out under the action of a ketone carbonyl protecting reagent and an acid catalyst.
10. The method of claim 9, wherein: the ketone carbonyl protecting reagent is selected from trimethyl orthoformate, triethyl orthoformate, tetramethyl orthocarbonate, tetraethyl orthocarbonate, trimethyl orthoacetate or triethyl orthoacetate; the acid catalyst is selected from p-toluenesulfonic acid and methanesulfonic acid.
11. The method of claim 7, wherein: the molar ratio of the compound of the general formula II to the 1, 4-cyclohexanedione is 2-10:1, preferably 2-3: 1.
12. The production method according to claim 9 or 10, characterized in that: the molar ratio of the 1, 4-cyclohexanedione to the ketone carbonyl protecting agent is 1:2-10, preferably 1: 2-3.
13. The production method according to claim 9 or 10, characterized in that: the molar ratio of the 1, 4-cyclohexanedione to the acid catalyst is 1:0.001-0.1, preferably 1: 0.02-0.05.
14. A process for the preparation of a compound as claimed in claims 1 to 6, characterized in that: reacting a compound shown as a general formula III with 1, 4-cyclohexanedione in a solvent;
wherein X and R have the same meanings as X and R in the formula I, respectively.
15. The method of claim 14, wherein: the solvent is selected from toluene, dichloromethane, tetrahydrofuran, acetonitrile, methanol or ethanol.
16. The method of claim 14, wherein: the reaction system is carried out under the action of a catalyst, and the catalyst is selected from p-toluenesulfonic acid and methanesulfonic acid.
17. The method of claim 14, wherein: the molar ratio of the compound in the general formula III to the 1, 4-cyclohexanedione is 2-10:1, preferably 2-3: 1.
18. The method of claim 16, wherein: the molar ratio of the 1, 4-cyclohexanedione to the catalyst is 1:0.001-0.1, preferably 1: 0.02-0.05.
19. Use of a compound according to any one of claims 1 to 6 in the preparation of a statin.
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CN109824605A (en) * 2019-03-14 2019-05-31 浙江永太科技股份有限公司 The synthetic method of rosuvastain calcium
CN109836386A (en) * 2019-03-13 2019-06-04 浙江永太药业有限公司 The synthesis technology of rosuvastain calcium

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