A method for synthesizing the key intermediate of rosuvastatin calcium

A technology of rosuvastatin calcium and asana, which is applied in the field of statin drugs, can solve the problems of energy consumption, high equipment and production costs, unfavorable industrial production, and high price, and achieve low price, easy large-scale production, and health hazards low effect

Active Publication Date: 2018-01-23
重庆瑞泊莱医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] This process uses expensive 4-methylmorpholine-N-oxide, TPAP (tetrapropylammonium perruthenate) and DIBAL-H, and DIBAL-H reduction needs to be reacted at low temperature (-70~-40 ℃), energy consumption, equipment and production costs will be very large, which is not conducive to industrial production

Method used

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  • A method for synthesizing the key intermediate of rosuvastatin calcium
  • A method for synthesizing the key intermediate of rosuvastatin calcium
  • A method for synthesizing the key intermediate of rosuvastatin calcium

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Synthesis of 1-(4-fluorophenyl)-4-methylpentane-1,3-dione (compound IV)

[0030]

[0031] Add 150g of ethanol to a 0.5L three-neck flask, then add 6.9g of sodium ethylate in batches, stir vigorously after the sodium ethylate dissolves completely, add 13.81g (0.1mol) of p-fluoroacetophenone and 11.62g of ethyl isobutyrate dropwise (0.1mol) dissolved in 80g ethanol solution. The reaction solution was refluxed at 82° C. for 6 h, then cooled to room temperature, and stirred overnight. A large amount of product was precipitated, filtered to obtain an off-white product, and dried in a blast oven at 40°C to constant weight to obtain 18g, with a yield of 86%. NMR data (1HNMR, 500MHz, internal standard TMS, solvent CDCl3) is as follows: 1.30 (d, J=7.0Hz, 6H, CH 3 ), 2.61(m, 1H, CH), 4.15(s, 1H, CH 2 ), 7.18-7.12 (m, 2H, Ar-H), 7.93-7.87 (m, 2H, Ar-H).

Embodiment 2

[0032] Example 2: Synthesis of 4-(4-fluorophenyl)-6-isopropyl-N-methylpyrimidin-2-amine (compound III)

[0033]

[0034] Add 10.4g (0.05mol) of compound IV, 6g (0.055mol) of methylguanidine hydrochloride, 8.4g (0.15mol) of potassium hydroxide, and 100ml of acetone into a 250ml three-necked flask, and heat up to reflux overnight. After the reaction was completed, the acetone was distilled off under reduced pressure, naturally cooled to 10°C, filtered, and a small amount of acetone rinsed the filter cake, and the obtained filter cake was dried in a vacuum oven at 50°C to constant weight. 11.4 g of off-white solid was obtained with a yield of 93%. NMR data (1HNMR, 500MHz, internal standard TMS, solvent DMSO) are as follows: 1.25(d, J=6.8Hz, 6H, CH 3 ), 2.98 (d, 3H, CH 3 ), 3.18(m, 1H, CH), 4.98(s, 1H, NH), 6.71(s, 1H, Ar-H), 7.16~7.10(m, 2H, Ar-H), 7.52~7.47(m, 2H, Ar-H).

Embodiment 3

[0035] Example 3: Synthesis of 4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine (Compound II)

[0036]

[0037] Under nitrogen protection, 9.8 g (0.04 mol) of compound III and 100 ml of toluene were added to a 250 ml three-neck flask, and cooled to 5°C. , Add 12.1g (0.12mol) triethylamine, stir and react for half an hour. A solution of 5.5 g (0.048 mol) of methanesulfonyl chloride dissolved in 5 ml of toluene was slowly added dropwise to the reaction liquid, and the reaction was continued with stirring at 0-25° C. for 12 h. After the reaction was completed, 20ml of toluene was added, 30ml of purification was added, concentrated hydrochloric acid was added to adjust the pH to 2-3, and the organic layer was obtained by layering. The obtained organic layer was washed once with 50 ml of saturated brine, dried with 10 g of anhydrous sodium sulfate, and filtered. Toluene was removed by desolvation under reduced pressure, 50ml of methanol was added t...

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PUM

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Abstract

The invention discloses a method used for synthesizing a rosuvastatin calcium intermediate represented by formula I. The reaction route is disclosed in the invention. Raw materials used in the method are low in toxicity; synchronous recycling of used solvents can be realized; expensive materials such as 4-methylmorpholine-N-oxide, TPAP (tetrapropylammonium perruthenate), and DIBAL-H are not used, so that production cost is reduced effectively; reaction conditions are mild; energy consumption is low; no special reaction equipment is needed; operation is simple; one-pot preparation can be realized; and the method is convenient for large-scale production.

Description

technical field [0001] The invention relates to statin drugs, in particular to a method for synthesizing a key intermediate of rosuvastatin calcium. Background technique [0002] Rosuvastatin calcium, chemical name: (3R, 5S, 6E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) )-5-pyrimidine]-3,5-dihydroxy-6-heptenoic acid calcium, as a kind of IMG-CoA inhibitor, is used for the treatment of cardiovascular disease, has potent, high safety, few side effects, tolerance The characteristics of good sex play an important role in reducing the risk of cardiovascular disease. [0003] 5-(Formyl)-4-(4-fluorophenyl)-6-isopropyl-2-[(N-methyl-N-methylsulfonyl)amino]pyrimidine is a synthetic rosuvastatin calcium Important intermediate, its structural formula is as follows (formula I): [0004] [0005] Patent EP521471A discloses a synthetic method of rosuvastatin calcium, which involves the preparation method of the intermediate, and the main steps of the proce...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42
Inventor 钟齐昌陈琳高河勇冉勇
Owner 重庆瑞泊莱医药科技有限公司
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