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Preparation method of rosuvastatin calcium intermediate

A technology for rosuvastatin calcium and intermediates, which is applied in the field of pharmaceutical synthesis, can solve the problems of increased synthesis steps and production costs, unsuitable for industrial production, harsh reaction conditions, etc., to avoid adverse effects, clean reaction, and mild reaction conditions Effect

Inactive Publication Date: 2017-10-10
SUZHOU HEALTH COLLEGE
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] (1) In the process of preparing compound 6 by oxidation of compound 5, a large amount of nitric acid is used as an oxidizing agent, which causes great environmental pollution, and post-treatment requires a large amount of lye to neutralize, resulting in low production efficiency;
[0011] (2) In the process of obtaining the target compound 1 by the reduction of compound 7, there are mainly two methods. The first method is to hydrolyze compound 7 to acid first, and then use potassium borohydride to reduce it to alcohol. This method increases the synthesis steps and Cost of production
The second method requires the direct reduction of compound 7 with diisobutylaluminum hydride (DIBAL-H) ​​at a low temperature of -78 ° C. This method has harsh reaction conditions and is not suitable for industrial production

Method used

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  • Preparation method of rosuvastatin calcium intermediate
  • Preparation method of rosuvastatin calcium intermediate
  • Preparation method of rosuvastatin calcium intermediate

Examples

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Embodiment 1

[0034] 1.1 Preparation of formula II compound 5

[0035] Add methanol, 24.8g (0.2mol) of p-fluorobenzaldehyde, 28.8g (0.2mol) of methyl isobutyryl acetate, 21g (0.35mol) of urea, and 0.2g (0.002mol) of cuprous chloride into a 1000mL three-necked flask and 2mL of 1mol / L sulfuric acid, heated to 78°C for 9h, stirred at 0°C for 2h in an ice-water bath, filtered, washed 3 times with cold ethanol, and dried at 65°C to obtain 55.3g of compound 5, yield 94.5%, mp: 224~ 225°C. 1 H-NMR (CDCl 3 ,400MHz)δ:1.18~1.23(d,6H,CH 3 ×2),3.62(s,3H,CH 3 ), 4.13~4.16(m,1H,CHCH 3 CH 3 ),5.30(d,1H,CHNH),5.54(d,1H,CHNH), 6.86(s,1H,NH),6.99~7.02(m,2H,ArH),7.26~7.29(m,2H,ArH) .

[0036] 1.2 Synthesis of Formula III Compound 6

[0037] 55g (0.19mol) of compound 5, 50.8g (0.19mol) of potassium persulfate, 300ml of acetonitrile, and 60ml of water were added sequentially to a 500mL three-necked flask, heated to reflux, and stirred for 5h. After the reaction is complete, evaporate acetonitrile under...

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Abstract

The invention provides a preparation method of a rosuvastatin calcium intermediate. The preparation method of the rosuvastatin calcium intermediate, namely, the compound shown as formula I in the description comprises the following steps: (1) a compound 5 shown as formula II in the description is generated from 4-fluorobenzaldehyde, methyl isobutyrylacetate and urea under the action of a catalyst; (2) a compound 6 shown as formula III in the description is generated from the compound 5 under the action of potassium persulfate as an oxidizing agent; (3) a compound 7 shown as formula IV in the description is generated from the compound 6, tosyl chloride and N-methyl methanesulfonamide under the action of a catalyst; (4) the target compound shown as the formula I is generated from the compound 7 under the action of a vitride solution as a reducing agent and crystallized with a crystallization solution, and a purified target compound is obtained. The preparation method of the rosuvastatin calcium intermediate has the advantages of low production cost, mild condition and simple and convenient operation.

Description

technical field [0001] The invention relates to the field of medicine synthesis, in particular to a preparation method of a rosuvastatin calcium intermediate. Background technique [0002] Rosuvastatin Calcium (Rosuvastatin Calcium), chemical name: bis-[E-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino ]-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt, is a kind of statin hypolipidemic drug, belongs to hydroxymethylglutaryl coenzyme A ( HMG-CoA) reductase inhibitors. Rosuvastatin Calcium was purchased from Shionogi Pharmaceutical Co., Ltd., Japan. This product can significantly increase HDL-C while lowering LDC-C. Compared with other statins on the market, rosuvastatin calcium has better pharmacology in terms of HMG-COA reductase inhibition It has the advantages of low toxicity and side effects, and is known as "super statin". [0003] For the synthesis of rosuvastatin calcium, its important intermediate 4-(4-fluorophenyl)-6-isopropyl...

Claims

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Application Information

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IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 张立光龚逸奕丁荣敏
Owner SUZHOU HEALTH COLLEGE
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