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Preparation methods for rosuvastatin calcium and intermediates thereof

A technology of rosuvastatin and intermediates, applied in the field of drug synthesis, which can solve the problems of unsuitability for industrial application, transportation, storage, use and post-processing of n-butyllithium, etc.

Active Publication Date: 2014-01-01
SHANGHAI DESANO PHARMA INVESTMENT +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] This method also uses the side chain compound 20. Although the temperature of the Wittig reaction has been increased (-25~-40°C can be used), refrigeration equipment is still required, and a large amount of 2,2,6,6 - Tetramethylpiperidine (4-5 times more molar than the substrate for this reaction), and n-butyllithium, which is dangerous to transport, store, use and work up and is therefore also unsuitable Industrial application

Method used

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  • Preparation methods for rosuvastatin calcium and intermediates thereof
  • Preparation methods for rosuvastatin calcium and intermediates thereof
  • Preparation methods for rosuvastatin calcium and intermediates thereof

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preparation example Construction

[0061] The present invention provides an intermediate compound for preparing rosuvastatin calcium shown in formula II, the structure of which is as follows:

[0062]

[0063] The compound of formula II used in the present invention can be prepared by conventional methods in the art, and can also be preferably prepared by the following steps: 1～4 In a halogenated hydrocarbon solvent (such as dichloromethane, chloroform, or a combination thereof), at a certain temperature (such as -5 ~ 30 ° C, preferably 0 ~ 25 ° C), the compound of formula I and form The sulfonyl chloride is reacted for a period of time (eg, 2-8 hours or 3-5 hours) to form a compound of formula II.

[0064]

[0065] The intermediate shown in formula III

[0066] The present invention provides an intermediate compound for preparing rosuvastatin calcium shown in formula III, the structure of which is as follows:

[0067]

[0068] The compound of formula III used in the present invention can be prepared...

Embodiment 1

[0126] 1.1 Preparation of formula II compound

[0127] Add formula I compound (29.0g, 0.10mol), dichloromethane 300ml, triethylamine (12.2g, 0.12mol) into the reaction flask, cool down to 0°C, slowly add methanesulfonyl chloride (12.5g, 0.11mol) ). After the addition, it was raised to room temperature and reacted for 4 hours. After the reaction was complete, 300ml of water was added and stirred for 15 minutes. The layers were separated, and the organic layer was washed successively with saturated ammonium chloride solution and saturated brine, and anhydrous MgSO 4 Dry and concentrate to dryness under reduced pressure to obtain 35.0 g of white solid with a yield of 94.9%. MS (ESI) m / z: (M+H) = 369.4.

[0128] 1.2 Preparation of Formula III Compound

[0129] Add the compound of formula II (35.0g, 0.095mol) and 350ml of toluene into the reaction bottle, cool down to -10°C, slowly add 95ml of 2mol / L diisobutylaluminum hydride (DIBAl-H) toluene solution dropwise, and finish th...

Embodiment 2

[0141] 2.1 Preparation of formula II compound

[0142] Add the compound of formula I (15.0g, 0.052mol), 150ml of dichloromethane, and pyridine (4.7g, 0.059mol) into the reaction flask, cool down to 0°C, and slowly add methanesulfonyl chloride (8.6g, 0.073mol) dropwise. After the addition, it was raised to room temperature and reacted for 4 hours. After the reaction was complete, 300ml of water was added and stirred for 15 minutes. The layers were separated, and the organic layer was washed successively with saturated ammonium chloride solution and saturated brine, and anhydrous MgSO 4 Dry and concentrate to dryness under reduced pressure to obtain 18.4 g of white solid with a yield of 96.7%. MS (ESI) m / z: (M+H) = 369.4.

[0143] 2.2 Preparation of Formula III Compound

[0144] Add the compound of formula II (18.4g, 0.050mol) and 200ml of toluene into the reaction bottle, cool down to -10°C, slowly add 60ml of toluene solution of 2mol / L lithium aluminum hydride dropwise, an...

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Abstract

The present invention relates to preparation methods for rosuvastatin calcium and intermediates thereof, and specifically discloses intermediate compounds for preparing rosuvastatin calcium, and preparation methods thereof, wherein the structures of the intermediates are respectively represented by a formula II, a formula III, a formula IV, a formula VI and a formula VII in an instruction. The present invention further discloses a preparation method for rosuvastatain or a salt thereof, wherein the preparation method is based on the preceding five intermediate compounds and the preparation methods thereof, has characteristics of simple and safe operation and low production cost, and is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a preparation method of rosuvastatin calcium and an intermediate thereof. Background technique [0002] Rosuvastatin Calcium (Rosuvastatin Calcium) was developed by Shionogi Co., Ltd., Japan, and its chemical name is: [S-[R,S-(E)]]-7-[4-(4-Fluorophenyl)- Calcium 6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoate (the molar ratio of acid to calcium ion is 2:1), the structure is as follows: [0003] [0004] Rosuvastatin Calcium is a fully synthetic single enantiomer of a new generation of statin blood lipid regulators, belonging to HMG-CoA reductase inhibitors, can reduce elevated low-density cholesterol, total cholesterol, triglycerides and detoxification Concentration of prosthetic protein B, while increasing the concentration of high-density cholesterol. It can be used for the comprehensive treatment of primary h...

Claims

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Application Information

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IPC IPC(8): C07D239/34C07D405/06
CPCC07D239/34C07D239/42C07D405/06
Inventor 李金亮赵楠熊毅
Owner SHANGHAI DESANO PHARMA INVESTMENT
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